Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions

ABSTRACT

The present invention relates to the CGRP-antagonists of general formula I 
                         
wherein R 1 , R 2 , R 3  and R 4  are defined as in claim  1,  the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates thereof, the mixtures thereof and the salts thereof and the hydrates of the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, as well as those compounds of general formula I wherein one or more hydrogen atoms are replaced by deuterium, pharmaceutical compositions containing these compounds, their use and processes for preparing them.

The present invention relates to CGRP antagonists of general formula I

wherein R¹, R², R³ and R⁴ are as herein defined, the tautomers, theisomers, the diastereomers, the enantiomers, the hydrates thereof, themixtures thereof and the salts thereof and the hydrates of the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases, as well as those compounds ofgeneral formula I wherein one or more hydrogen atoms are replaced bydeuterium, pharmaceutical compositions containing these compounds, theiruse and processes for preparing them.

PRIOR ART

CGRP antagonists for the treatment of migraine have already beendescribed in International Patent Applications PCT/EP97/04862 andPCT/EP04/000087.

DETAILED DESCRIPTION OF THE INVENTION

In the above general formula I in a first embodiment

-   R¹ denotes a group selected from

wherein

-   -   R^(1.1) denotes H or H₃C—O—,

-   R² denotes a group of general formula II

wherein

-   -   R^(2.1) denotes HO, H₃CO, H—C(O)—O or H₃C—C(O)—O— and    -   R^(2.2) denotes C₁₋₂-alkyl or H₃CO—,

-   R³ denotes R⁴—C₂₋₈-alkylene-NH—and

-   R⁴ denotes H, H₂N, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂—N or    C₁₋₆-alkyl-O—C(O)—NH—, or

-   R³ denotes a group of general formulae III

wherein

-   -   R^(3.2) denotes H or C₁₋₃-alkyl,    -   R^(3.3) denotes a free electron pair or an oxygen atom,    -   R^(3.4) denotes H or C₁₋₃-alkyl-, and

-   R⁴ denotes H, C₁₋₆-alkyl, H₂N—C₂₋₆-alkylene,    C₁₋₃-alkyl-NH—C₂₋₆-alkylene, (C₁₋₃-alkyl)₂—N—C₁₋₆-alkylene,    C₃₋₆-cycloalkyl-C₁₋₃-alkylene, NH₂, C₁₋₃-alkyl-NH or    (C₁₋₃-alkyl)₂—N, or

-   R⁴ denotes a group selected from

-   R⁴ denotes a group of general formulae IV

wherein

-   -   X denotes C and    -   R^(4.1) denotes H, OH or C₁₋₃-alkyl, or    -   X denotes N and    -   R^(4.1) denotes a free electron pair or an oxygen atom,    -   Y denotes O, S, S(O), S(O)₂, if X═N, or    -   Y denotes S, S(O), S(O)₂, if X═C,    -   R^(4.2) denotes H or C₁₋₃-alkyl,    -   R^(4.3) denotes H or C₁₋₃-alkyl,    -   R^(4.4) denotes a free electron pair or, if R^(5.2) is not H or        C₁₋₃-alkyl-C(O)—, an oxygen atom,    -   R^(5.1) denotes H, CN, OH, C₁₋₃-alkyl, C₁₋₃-alkyl-C(O)—O,        C₁₋₃-alkyl-O, R^(5.1,1)—O—C(O), R ^(5.1.1)—C(O)—C₂₋₄-alkylene or        R^(5.1,1)—O—C(O)—C₁₋₃-alkylene-O,    -   R^(5.1.1) denotes H, C₁₋₆-alkyl, H₂N—C(O)—C₁₋₃-alkylene,        C₁₋₃-alkyl-NH—C(O)—C₁₋₃-alkylene,        (C₁₋₃-alkyl)₂—N—C(O)—C₁₋₃-alkylene or        C₁₋₃-alkyl-O—C(O)—O—C₁₋₃-alkylene, or    -   R^(5.2) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,        C₃₋₆-cycloalkyl-C₁₋₃-alkylene, C₁₋₃-alkyl-C(O),        R^(5.2.1)—C(O)—C₁₋₃-alkylene or    -   R^(5.2.2)—C₂₋₄-alkylene-O—C(O)—C₁₋₃-alkylene,    -   R^(5.2.1) denotes H, C₁₋₆-alkyl,        C₁₋₆-alkyl-C(O)—O—C₁₋₃-alkylene,        C₁₋₃-alkyl-O—C(O)—O—C₁₋₃-alkylene,        C₃₋₇-cycloalkyl-O—C(O)—O—C₁₋₃-alkylene, H₂N—C(O)—C₁₋₃-alkylene,        C₁₋₃-alkyl-NH—C(O)—C₁₋₃-alkylene,        (C₁₋₃-alkyl)₂—N—C(O)—C₁₋₃-alkylene or    -   R^(5.2.1.1)—C(O)—C₁₋₃-alkylene and    -   R^(5.2.1.1) denotes a group selected from

-   -   R^(5.2.1) denotes a group selected from

-   -   R^(5.2.2) denotes H₂N, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂—N,        C₁₋₃-alkyl-O or C₁₋₃-alkyl-O—C₂₋₄-alkylene-O, or    -   R^(5.2.2) denotes a group selected from

with the proviso that R³ and R⁴ are not bound to one anothersimultaneously via an N atom,the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof and the hydrates of the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

A preferred first embodiment of the present invention comprises thecompounds of the above general formula 1, wherein

R¹, R², R³ and R⁴ are as hereinbefore defined in the first embodiment,with the proviso that the compounds

-   (a)    (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (b)    (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carboxylate,-   (c) (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(1′-methyl    -4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (d)    (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (e)    (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (f)    (R)-2-4,4′-bipiperidinyl-1-yl-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (g)    (R)-2-1,4′-bipiperidinyl-1′-yl-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (h)    (R)-2-(4-dimethylamino-piperidin-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (i)    (R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (k)    (R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (k) (R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-(1′-methyl    -4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (l)    (R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (m)    (R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (n)    (R)-2-4,4′-bipiperidinyl-1-yl-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (o)    (R)-2-1,4′-bipiperidinyl-1′-yl-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (p)    (R)-2-(4-dimethylamino-piperidin-1-yl)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (q)    (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (r)    (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (s)    (R)-2-(4.4-dimethyl-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (t)    (R)-2-(4-hydroxy-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (u)    (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-hydroxy-4-methyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (v)    (R)-2-(4-ethyl-4-hydroxy-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (w)    (R)-2-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (x)    (R)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (y)    (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (z)    (R)-2-[4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (aa)    (R)-2-[4-(4-carboxymethyl-piperazin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (ab)    (R)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (ac)    (R)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (ad)    (R)-2-[1′-(2-ethoxycarbonyl-ethyl)-4,4′-bipiperidinyl-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (ae)    (R)-2-[1′-(2-carboxy-ethyl)-4,4′-bipiperidinyl-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (af)    (R)-2-{4-[1-(2-ethoxycarbonyl-ethyl)-piperidin-4-yl]-piperazin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (ag)    (R)-2-{4-[1-(2-carboxy-ethyl)-piperidin-4-yl]-piperazin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (ah)    (R)-2-{4-[4-(2-ethoxycarbonyl-ethyl)-piperazin-1-yl]-piperidin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (ai)    (R)-2-{4-[4-(2-carboxy-ethyl)-piperazin-1-yl]-piperidin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,    are excluded from the scope of protection,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof and the hydrates of the salts    thereof, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

In the above general formula I in a second embodiment

-   R¹ denotes a group selected from

wherein

-   -   R^(1.1) denotes H or H₃C—O—,

-   R² denotes a group of general formula II

wherein

-   -   R^(2.1) denotes HO, H₃CO, H—C(O)—O or H₃C—C(O)—O— and    -   R^(2.2) denotes C₁₋₂-alkyl or H₃CO—,

-   R³ denotes R⁴—C₂₋₈-alkylene-NH— and    -   R⁴ denotes H₂N, C₁₋₃-alkyl-NH or (C₁₋₃-alkyl)₂—N,        C₁₋₆-alkyl-O—C(O)—NH—, or

-   R³ denotes a group of general formulae III

wherein

-   -   R^(3.2) denotes H,    -   R^(3.3) denotes a free electron pair or an oxygen atom,    -   R^(3.4) denotes H or C₁₋₃-alkyl, and

-   R⁴ denotes H, C₁₋₆-alkyl, H₂N—C₂₋₆-alkylene,    C₁₋₃-alkyl-NH—C₂₋₆-alkylene, (C₁₋₃-alkyl)₂—N—C₁₋₆-alkylene,    C₃₋₆-cycloalkyl-C₁₋₃-alkylene, H₂N, C₁₋₃-alkyl-NH or    (C₁₋₃-alkyl)₂—N, or

-   R⁴ denotes a group selected from

-   R⁴ denotes a group of general formulae IV

wherein

-   -   X denotes C and    -   R^(4.1) denotes H, OH, C₁₋₃-alkyl or    -   X denotes N and    -   R^(4.1) denotes a free electron pair or an oxygen atom,    -   Y denotes O, S, S(O), S(O)₂, if X═N, or    -   Y denotes S, S(O), S(O)₂, if X═C,

-   R^(4.2) denotes H,

-   R^(4.3) denotes H or C₁₋₃-alkyl,

-   R^(4.4) denotes a free electron pair or, if R^(5.2) is not H or    C₁₋₃-alkyl-C(O)—, an oxygen atom,

-   R^(5.1) denotes H, CN, OH, C₁₋₃-alkyl, C₁₋₃-alkyl-C(O)—O,    C₁₋₃-alkyl-O, R^(5.1,1)—O—C(O), R ^(5.1.1)—O—C(O)—C₂₋₄-alkylene or    R^(5.1,1)—O—C(O)—C₁₋₃-alkylene-O,

-   R^(5.1.1) denotes H, C₁₋₆-alkyl, H₂N—C(O)—C₁₋₃-alkylene,    C₁₋₃-alkyl-NH—C(O)—C₁₋₃-alkylene, (C₁₋₃-alkyl)₂—N—C(O)—C₁₋₃-alkylene    or C₁₋₃-alkyl-O—C(O)—O—C₁₋₃-alkylene,

-   R^(5.2) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,    C₃₋₆-cycloalkyl-C₁₋₃-alkylene, C₁₋₃-alkyl-C(O),    R^(5.21)—O—C(O)—C₁₋₃-alkylene or    R^(5.2.2)—C₂₋₄-alkylene-O—C(O)—C₁₋₃-alkylene,

-   R^(5.2.1) denotes H, C₁₋₆-alkyl, C₁₋₆-alkyl-C(O)—O—C₁₋₃-alkylene,    C₁₋₃-alkyl-O—C(O)—O—C₁₋₃-alkylene,    C₃₋₇-cycloalkyl-O—C(O)—O—C₁₋₃-alkylene, H₂N—C(O)—C₁₋₃-alkylene,    C₁₋₃-alkyl-NH—C(O)—C₁₋₃-alkylene, (C₁₋₃-alkyl)₂—N—C(O)—C₁₋₃-alkylene    or R^(5.2.1.1)—C(O)—C₁₋₃-alkylene and

-   R^(5.2.1.1) denotes a group selected from

-   R^(5.2.1) denotes a group selected from

-   -   R^(5.2.2) denotes H₂N, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂—N,        C₁₋₃-alkyl-O or C₁₋₃-alkyl-O—C₂₋₄-alkylene-O, or    -   R^(5.2.2) denotes a group selected from

with the proviso that R³ and R⁴ are not bound to one anothersimultaneously via an N atom,the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof and the hydrates of the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

A third embodiment of the present invention comprises the compounds ofthe above general formula I, wherein

-   R¹ denotes a group selected from

-   R² denotes a group selected from

-   R³ denotes R⁴—C₂₋₈-alkylene-NH— and    -   R⁴ denotes H, H₂N, (C₁₋₃-alkyl)₂—N or C₁₋₄-alkyl-O—C(O)—NH—, or-   R³ denotes a group selected from

and

-   R⁴ denotes H, C₁₋₆-alkyl, (C₁₋₃-alkyl)₂—N—C₁₋₆-alkylene,    C₃₋₆-cycloalkyl-C₁₋₃-alkylene or (C₁₋₃-alkyl)₂—N, or-   R⁴ denotes a group selected from

-   R⁴ denotes a group selected from

wherein

-   -   Y denotes O, S, S(O), S(O)₂,    -   R^(4.4) denotes a free electron pair or, if R^(5.2) is not H or        C₁₋₃-alkyl-C(O)—, an oxygen atom,    -   R^(5.1) denotes H, CN, OH, C₁₋₃-alkyl, C₁₋₃-alkyl-C(O)—O,        C₁₋₃-alkyl-O, R^(5.1,1)—O—C(O), R^(5.1,1)—O—C(O)—C₂₋₄-alkylene        or R^(5.1,1)—O—C(O)—C₁₋₃-alkylene-O,    -   R^(5.1.1) denotes H, C₁₋₆-alkyl, H₂N—C(O)—C₁₋₃-alkylene,        C₁₋₃-alkyl-NH—C(O)—C₁₋₃-alkylene,        (C₁₋₃-alkyl)₂—N—C(O)—C₁₋₃-alkylene or        C₁₋₃-alkyl-O—C(O)—O—C₁₋₃-alkylene,    -   R^(5.2) denotes H, C₁₋₃-alkyl, cyclopropyl,        cyclopropyl-methylene, C₁₋₃-alkyl-C(O),        R^(5.2.1)—O—C(O)—C₁₋₃-alkylene or        R^(5.2.2)—C₂₋₄-alkylene-O—C(O)—C₁₋₃-alkylene,    -   R^(5.2.1) denotes H, C₁₋₆-alkyl,        C₁₋₆-alkyl-C(O)—O—C₁₋₃-alkylene,        C₁₋₃-alkyl-O—C(O)—O—C₁₋₃-alkylene,        (C₁₋₃-alkyl)₂—N—C(O)—C₁₋₃-alkylene or        R^(5.2.1,1)—C(O)—C₁₋₃-alkylene and    -   R^(5.2.1.1) denotes a group selected from

or

-   -   R^(5.2.1) denotes a group selected from

-   -   R^(5.2.2) denotes (C₁₋₃-alkyl)₂—N, C₁₋₃-alkyl-O or        C₁₋₃-alkyl-O—C₂₋₄-alkylene-O, or    -   R^(5.2.2) denotes a group selected from

with the proviso that R³ and R⁴ are not bound to one anothersimultaneously via an N atom,the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof and the hydrates of the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

A fourth embodiment of the present invention comprises the compounds ofthe above general formula I, wherein

-   R¹ denotes a group selected from

-   R² denotes a group selected from

-   R³-R⁴ together denote a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof and the hydrates of the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

A fifth embodiment of the present invention comprises the compounds ofthe above general formula I, wherein

-   R¹ denotes a group selected from

-   R² denotes a group selected from

-   R³-R⁴ together denote a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof and the hydrates of the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

A sixth embodiment of the present invention comprises the compounds ofthe above general formula I, wherein

-   R¹ denotes a group

and R², R³ and R⁴ are as hereinbefore defined in the first embodiment,the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof and the hydrates of the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

A seventh embodiment of the present invention comprises the compounds ofthe above general formula I, wherein

-   R¹ denotes a group

and R², R³ and R⁴ are as defined in the first embodiment hereinbefore,the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof and the hydrates of the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

An eighth embodiment of the present invention comprises the compounds ofthe above general formula I, wherein

-   R¹ denotes a group

and R², R³ and R⁴ are as defined in the first embodiment hereinbefore,with the proviso that the compounds

-   (a)    (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-    piperidine-1-carboxylate,-   (b)    (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (c) (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(1′-methyl    -4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (d)    (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (e)    (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (f)    (R)-2-4,4′-bipiperidinyl-1-yl-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (g)    (R)-2-1,4′-bipiperidinyl-1′-yl-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (h)    (R)-2-(4-dimethylamino-piperidin-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (i)    (R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (j)    (R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (k) (R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-(1′-methyl    -4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (l)    (R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (m)    (R)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (n)    (R)-2-4,4′-bipiperidinyl-1-yl-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (o)    (R)-2-1,4′-bipiperidinyl-1′-yl-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (p)    (R)-2-(4-dimethylamino-piperidin-1-yl)-1-(4-methoxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (q)    (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (r)    (R)-2-(4-cyclohexyl-piperazin-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (s)    (R)-2-(4.4-dimethyl-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (t)    (R)-2-(4-hydroxy-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (u)    (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-hydroxy-4-methyl-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (v)    (R)-2-(4-ethyl-4-hydroxy-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (w)    (R)-2-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (x)    (R)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (y)    (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (z)    (R)-2-[4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (aa)    (R)-2-[4-(4-carboxymethyl-piperazin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (ab)    (R)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (ac)    (R)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (ad)    (R)-2-[1′-(2-ethoxycarbonyl-ethyl)-4,4′-bipiperidinyl-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,

(ae)(R)-2-[1′-(2-carboxy-ethyl)-4,4′-bipiperidinyl-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,

-   (af)    (R)-2-{4-[1-(2-ethoxycarbonyl-ethyl)-piperidin-4-yl]-piperazin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (ag)    (R)-2-{4-[1-(2-carboxy-ethyl)-piperidin-4-yl]-piperazin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (ah)    (R)-2-{4-[4-(2-ethoxycarbonyl-ethyl)-piperazin-1-yl]-piperidin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,-   (ai)    (R)-2-{4-[4-(2-carboxy-ethyl)-piperazin-1-yl]-piperidin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl    4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,    are excluded from the scope of protection,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof and the hydrates of the salts    thereof, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

The following compounds are mentioned as examples of most particularlypreferred compounds of the above general formula I:

No. Structure (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

(46)

(47)

(48)

(49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

(58)

(59)

(60)

(61)

(62)

(63)

(64)

(65)

(66)

(67)

(68)

(69)

(70)

(71)

(72)

(73)

(74)

(75)

(76)

(77)

(78)

(79)

(80)

(81)

(82)

(83)

(84)

(85)

(86)

(87)

(88)

(89)

(90)

(91)

(92)

(93)

(94)

(95)

(96)

(97)

(98)

(99)

(100)

(101)

(102)

(103)

(104)

(105)

(106)

(107)

(108)

(109)

(110)

(111)

(112)

(113)

(114)

(115)

(116)

(117)

(118)

(119)

(120)

(121)

(122)

(123)

(124)

(125)

(126)

(127)

(128)

(129)

(130)

(131)

(132)

(133)

(134)

(135)

(136)

(137)

(138)

(139)

(140)

(141)

(142)

(143)

(144)

(145)

(146)

(147)

(148)

(149)

(150)

(151)

(152)

(153)

(154)

(155)

(156)

(157)

(158)

(159)

(160)

(161)

(162)

(163)

(164)

(165)

(166)

(167)

(168)

(169)

(170)

(171)

(172)

(173)

(174)

(175)

(176)

(177)

(178)

(179)

(180)

(181)

(182)

(183)

(184)

(185)

(186)

(187)

(188)

(189)

(190)

(191)

(192)

(193)

(194)

(195)

(196)

(197)

(198)

(199)

(200)

(201)

(202)

(203)

(204)

(205)

(206)

(207)

(208)

(209)

(210)

(211)

(212)

(213)

(214)

(215)

(216)

(217)

(218)

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof and the hydrates of the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

Terms and Definitions Used

Unless otherwise stated, all the substituents are independent of oneanother. If for example there are a plurality of C₁₋₆-alkyl groups assubstituents in one group, in the case of three C₁₋₆-alkyl substituents,independently of one another, one may represent methyl, one n-propyl andone tert-butyl.

Within the scope of this application, in the definition of possiblesubstituents, these may also be represented in the form of a structuralformula. If present, an asterisk (*) in the structural formula of thesubstituent is to be understood as being the linking point to the restof the molecule.

The subject-matter of this invention also includes the compoundsaccording to the invention, including the salts thereof, wherein one ormore hydrogen atoms, for example one, two, three, four or five hydrogenatoms, are replaced by deuterium.

By the term “C₁₋₂-alkyl” (including those which are part of othergroups) are meant alkyl groups with 1 or 2 carbon atoms, by the term“C₁₋₃-alkyl” are meant branched and unbranched alkyl groups with 1 to 3carbon atoms, and by the term “C₁₋₆-alkyl” are meant branched andunbranched alkyl groups with 1 to 6 carbon atoms. Examples include:methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl. The followingabbreviations may optionally also be used for the above-mentionedgroups: Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc.. Unless statedotherwise, the definitions propyl, butyl, pentyl and hexyl include allthe possible isomeric forms of the groups in question. Thus, forexample, propyl includes n-propyl and iso-propyl, butyl includesiso-butyl, sec-butyl and tert-butyl etc..

By the term “C₁₋₃-alkylene” (including those which are part of othergroups) are meant branched and unbranched alkylene groups with 1 to 3carbon atoms and by the term “C₂₋₄-alkylene” are meant branched andunbranched alkylene groups with 2 to 4 carbon atoms, by the term“C₁₋₆-alkylene” are meant branched and unbranched alkylene groups with 1to 6 carbon atoms, by the term “C₂₋₆-alkylene” are meant branched andunbranched alkylene groups with 2 to 6 carbon atoms, and by the term“C₁₋₈-alkylene” are meant branched and unbranched alkylene groups with 1to 8 carbon atoms. Examples include: methylene, ethylene, propylene,1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene,2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene,hexylene, heptylene or octylene. Unless stated otherwise, thedefinitions propylene, butylene, pentylene, hexylene, heptylene andoctylene include all the possible isomeric forms with the same number ofcarbons. Thus, for example, propylene also includes 1-methylethylene andbutylene includes 1-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene. It should also be mentioned that within the scopeof the present invention the terms “alkylene” and “alkylenyl” are usedsynonymously.

By the term “C₃₋₆-cycloalkyl” (including those which are part of othergroups) are meant cyclic alkyl groups with 3 to 6 carbon atoms and bythe term “C₃₋₇-cycloalkyl” are meant cyclic alkyl groups with 3 to 7carbon atoms. Examples of these include: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwise stated, thecyclic alkyl groups may be substituted by one or more groups selectedfrom among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine,chlorine, bromine and iodine.

Compounds of general formula I may have acid groups, mainly carboxylgroups, and/or basic groups such as e.g. amino functions. Compounds ofgeneral formula I may therefore be present as internal salts, as saltswith pharmaceutically useable inorganic acids such as for examplehydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid,sulphuric acid, methanesulphonic acid, ethanesulphonic acid,benzenesulphonic acid, p-toluenesulphonic acid or organic acids such asfor example malic acid, succinic acid, acetic acid, fumaric acid, maleicacid, mandelic acid, lactic acid, tartaric acid, citric acid or as saltswith pharmaceutically useable bases such as alkali or alkaline earthmetal hydroxides, e.g. sodium hydroxide or potassium hydroxide, orcarbonates, ammonia, zinc or ammonium hydroxides or organic amines suchas e.g. diethylamine, triethylamine, ethanolamine, diethanolamine,triethanolamine, cyclohexylamine, dicyclohexylamine, inter alia.

The compounds according to the invention may be present as racemates,provided that they have only one chiral element, but may also beobtained as pure enantiomers, i.e. in the (R) or (S) form. Compoundswhich are present as racemates or in the (R) form are preferred.

However, the application also includes the individual diastereomericpairs of antipodes or mixtures thereof, which are obtained if there ismore than one chiral element in the compounds of general formula I, aswell as the individual optically active enantiomers of which theabove-mentioned racemates are made up.

The invention relates to the compounds in question, optionally in theform of the individual optical isomers, mixtures of the individualenantiomers or racemates, in the form of the tautomers as well as in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids—such as for example acid additionsalts with hydrohalic acids—for example hydrochloric or hydrobromicacid—or organic acids—such as for example oxalic, fumaric, diglycolic ormethanesulphonic acid.

Methods of Preparation

The compounds of general formula I are prepared by methods known inprinciple. The following methods have proved particularly useful forpreparing the compounds of general formula I according to the invention:

(a) For preparing compounds of general formula I wherein all the groupsare as hereinbefore defined:

coupling a carboxylic acid of general formula V

wherein R¹ and R² are as hereinbefore defined, with an amine of generalformula VIH—R³-R⁴,wherein R³ and R⁴ are as hereinbefore defined, the linking taking placevia the nitrogen atom of R³.

Before the reaction is carried out any carboxylic acid functions,primary or secondary amino functions or hydroxy functions present in thegroups of the amine of formula H—R³-R⁴ may be protected by conventionalprotective groups and after the reaction has taken place any protectivegroups used may be cleaved again using methods familiar to those skilledin the art.

The coupling is preferably carried out using methods known from peptidechemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol.15/2), for example using carbodiimides such as e.g.dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) orethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)-N,N-N′,N′-tetramethyluronium hexafluorophosphate (HBTU) ortetrafluoroborate (TBTU) or1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt) the reactionspeed can be increased. The couplings are normally carried out withequimolar amounts of the coupling components as well as the couplingreagent in solvents such as dichloromethane, tetrahydrofuran,acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA),N-methylpyrrolidone (NMP) or mixtures thereof and at temperaturesbetween −30° C. and +30° C., preferably −20° C. and +25° C. Ifnecessary, N-ethyl-diisopropylamine (Hünig base) is preferably used asan additional auxiliary base.

The so-called “anhydride process” is used as a further coupling methodfor synthesising compounds of general formula I (cf. also: M. Bodanszky,“Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky,“Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27). TheVaughan variant of the “mixed anhydride process” is preferred (J. R.Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which the mixedanhydride of the carboxylic acid of general formula V which is to becoupled and monoisobutyl carbonate is obtained, using isobutylchlorocarbonate in the presence of bases such as 4-methylmorpholine or4-ethylmorpholine. The preparation of this mixed anhydride and thecoupling with the amines of general formula VI are carried out in aone-pot process, using the above-mentioned solvents and at temperaturesbetween −20° C. and +25° C., preferably 0° C. and +25° C.

(b) For preparing compounds of general formula I wherein all the groupsare as hereinbefore defined:

coupling a compound of general formula VII

wherein R¹ and R² are as hereinbefore defined and Nu denotes a leavinggroup, for example a halogen atom, such as the chlorine, bromine oriodine atom, an alkylsulphonyloxy group with 1 to 10 carbon atoms in thealkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy groupoptionally mono-, di- or trisubstituted by chlorine or bromine atoms, bymethyl or nitro groups, wherein the substituents may be identical ordifferent, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally substitutedby one or two methyl groups in the carbon skeleton, a1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl,a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl,pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, adimethylaminyloxy, 2(1H)-oxopyridin-1-yl-oxy, 2,5-dioxopyrrolidinpyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzotriazol-1-yloxy or azidegroup, with an amine of general formula VIH—R³-R⁴,wherein all the groups are as hereinbefore defined and the link iseffected via the nitrogen atom of the amine R³.

Before the reaction is carried out any carboxylic acid functions,primary or secondary amino functions or hydroxy functions present in thegroups of the amine of general formula VI may be protected byconventional protective groups and after the reaction has taken placeany protective groups used may be cleaved again using methods familiarto those skilled in the art.

The reaction is carried out under Schotten-Baumann or Einhornconditions, i.e. the components are reacted in the presence of at leastone equivalent of an auxiliary base at temperatures between −50° C. and+120° C., preferably −10° C. and +30° C., and optionally in the presenceof solvents. The auxiliary bases used are preferably alkali metal andalkaline earth metal hydroxides, e.g. sodium hydroxide, potassiumhydroxide or barium hydroxide, alkali metal carbonates, e.g. sodiumcarbonate, potassium carbonate or caesium carbonate, alkali metalacetates, e.g. sodium or potassium acetate, as well as tertiary amines,e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine,N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine,1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undec-7-ene, thesolvents used may be, for example, dichloromethane, tetrahydrofuran,1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide,N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkalineearth metal hydroxides, alkali metal carbonates or acetates are used asthe auxiliary bases, water may also be added to the reaction mixture ascosolvent.

The new compounds of general formula I according to the inventioncontain one or more chiral centres. If for example there are two chiralcentres present, the compounds may occur in the form of twodiastereomeric pairs of antipodes. The invention includes the individualisomers as well as the mixtures thereof.

The diastereomers may be separated on the basis of their differentphysico-chemical properties, e.g. by fractional crystallisation fromsuitable solvents, by high pressure liquid or column chromatography,using chiral or preferably non-chiral stationary phases.

Racemates covered by general formula I may be separated for example byHPLC on suitable chiral stationary phases (e.g. Chiral AGP, ChiralpakAD). Racemates which contain a basic or acidic function can also beseparated via the diastereomeric, optically active salts which areproduced on reacting with an optically active acid, for example (+) or(−)-tartaric acid, (+) or (−)-diacetyl tartaric acid, (+) or(−)-monomethyl tartrate or (+) or (−)-camphorsulphonic acid, or anoptically active base, for example with (R)-(+)-1-phenylethylamine,(S)-(−)-1-phenylethylamine or (S)-brucine.

According to a conventional method of separating isomers, the racemateof a compound of general formula I is reacted with one of theabovementioned optically active acids or bases in equimolar amounts in asolvent and the resulting crystalline, diastereomeric, optically activesalts thereof are separated using their different solubilities. Thisreaction may be carried out in any type of solvent provided that it issufficiently different in terms of the solubility of the salts.Preferably, methanol, ethanol or mixtures thereof, for example in aratio by volume of 50:50, are used. Then each of the optically activesalts is dissolved in water, carefully neutralised with a base such assodium carbonate or potassium carbonate, or with a suitable acid, e.g.with dilute hydrochloric acid or aqueous methanesulphonic acid, and inthis way the corresponding free compound is obtained in the (+) or (−)form.

The (R) or (S) enantiomer alone or a mixture of two optically activediastereomeric compounds covered by general formula I may also beobtained by performing the syntheses described above with a suitablereaction component in the (R) or (S) configuration.

The carboxylic acids of general formula V needed as starting compoundsmay be obtained by reacting piperidines of general formula VIII

wherein R¹ is as hereinbefore defined, with carbonic acid derivatives ofgeneral formula IX

wherein Y¹ and Y² represent nucleofugic groups, which may be identicalor different, preferably the chlorine atom, the p-nitrophenoxy ortrichloromethoxy group,and with compounds of general formula X

wherein R² is as hereinbefore defined and Z¹ denotes a protective groupfor a carboxy group, for example a C₁₋₆-alkyl or an optionallysubstituted benzyl group, wherein the alkyl groups may be straight-chainor branched and the benzyl group may be substituted by one or twomethoxy groups.

Preferably Z¹ denotes the methyl, ethyl, tert-butyl or benzyl group.Before the reaction is carried out any hydroxy functions present in thegroup R² of a compound of formula VI may be protected by conventionalprotective groups and after the reaction is complete any protectivegroups used may be cleaved again using methods familiar to the skilledman.

In a first step the compounds of general formula VIII are reacted withthe carbonic acid derivatives of general formula IX in a solvent, forexample in dichloromethane, THF, pyridine or mixtures thereof, at atemperature between −20° C. to 50° C. in the presence of a base, forexample triethylamine, pyridine or ethyldiisopropylamine. Theintermediate thus formed may be purified or reacted further withoutpurification. The reaction of these intermediates with compounds ofgeneral formula X also takes place in one of the above-mentionedsolvents and at the temperatures specified above, in the presence of abase, such as triethylamine or pyridine, with or without the addition ofan activating reagent, such as e.g. 4-dimethylaminopyridine. To activatethem the compounds of general formula X may also be deprotonated using ametal hydride, such as e.g. NaH or KH, while in this case there is noneed for the base or the activating reagent to be present.

The starting compounds of formula VIII and IX are either commerciallyobtainable, known from the literature or may be prepared using methodsknown from the literature.

One way of obtaining compounds of general formula X comprises reactingaldehydes of general formula XI

wherein R² is as hereinbefore defined, with N-acetylglycine in aceticanhydride as solvent in the presence of alkali metal acetate, preferablysodium or potassium acetate, at suitable temperatures, preferably at 80to 130° C.

The azlactones obtained as primary product are hydrolysed without beingisolated to form the compounds of general formula XII

wherein R² is as hereinbefore defined.

Alternatively enamides of the general structure XIII

wherein R² is as hereinbefore defined, may be obtained by a couplingreaction of compounds of general formula XIVHal-R²,wherein R² is as hereinbefore defined and Hal denotes the bromine oriodine atom, and methyl 2-acetylaminoacrylate.

The reaction is carried out in a suitable solvent such astetrahydrofuran, dimethylformamide, 1,4-dioxane or acetonitrile,preferably acetonitrile, at temperatures between ambient temperature and120° C., preferably between 50° C. and 80° C., in the presence of asuitable auxiliary base, such as triethylamine or ethyldiisopropylamine,preferably triethylamine, and a suitable catalyst system.

Suitable catalyst systems constitute the combination of a palladiumspecies, such as palladium(II)acetate or bis(acetonitrile)-palladiumdichloride, preferably palladium(II)acetate, and a suitable phosphaneligand, such as triphenyl- or tris-o-tolyl-phosphane, preferablytris-o-tolyl-phosphane. By further reaction of compounds of generalformulae XII and XIII in the presence of aqueous inorganic acids, suchas sulphuric, phosphoric or hydrochloric acid, but preferablyhydrochloric acid, compounds of general formula XV are obtained

wherein R² is as hereinbefore defined.

These are then converted with suitable reducing agents into thecompounds of general formula XVI

wherein R² is as hereinbefore defined.

Suitable reducing agents are alkali metal borohydrides, such as sodiumor potassium borohydride. Other suitable reducing agents arechlorodialkylboranes, such as chlorodicyclohexylborane. If chiralchlorodialkylboranes, such as e.g. B-chlorodiisopinocampheylborane, areused, the compounds of general formula XIV may be isolated inenantiomerically pure form. The further reaction of compounds of generalformula XIV to form compounds of general formula X is carried out in analcoholic medium, preferably in methanol or ethanol, in the presence ofa suitable acid, such as hydrochloric acid. Alternatively, the reactionmay be carried out by reacting with thionyl chloride in alcoholicsolvents, preferably methanol.

All the compounds of general formula I which contain primary orsecondary amino, hydroxy or hydroxycarbonyl functions are preferablyobtained from precursors with protective groups. Examples of protectivegroups for amino functions include a benzyloxycarbonyl,2-nitrobenzyloxycarbonyl, 4-nitro-benzyloxycarbonyl,4-methoxy-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl,3-chloro-benzyloxycarbonyl, 4-chloro-benzyloxycarbonyl,4-biphenylyl-α,α-dimethyl-benzyloxycarbonyl or3,5-dimethoxy-α,α-dimethyl-benzyloxycarbonyl group, an alkoxycarbonylgroup with a total of 1 to 5 carbon atoms in the alkyl moiety, forexample the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,iso-propoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl,2-methylpropoxy-carbonyl or tert-butyloxycarbonyl group, theallyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl or9-fluorenylmethoxycarbonyl group or a formyl, acetyl or trifluoracetylgroup.

Examples of protective groups for hydroxy functions include atrimethylsilyl, triethylsilyl, triisopropyl, tert-butyldimethylsilyl ortert-butyldiphenylsilyl group, a tert-butyl, benzyl, 4-methoxybenzyl or3,4-dimethoxybenzyl group.

Examples of protective groups for hydroxycarbonyl functions include analkyl group with a total of 1 to 5 carbon atoms, for example the methyl,ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, allyl,2,2,2-trichloroethyl, benzyl or 4-methoxybenzyl group.

The compounds of general formula I obtained may, if they containsuitable basic functions, be converted, particularly for pharmaceuticaluse, into their physiologically acceptable salts with inorganic ororganic acids. Suitable acids include for example hydrochloric acid,hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid,methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid,p-toluenesulphonic acid, acetic acid, fumaric acid, succinic acid,lactic acid, mandelic acid, malic acid, citric acid, tartaric acid ormaleic acid.

Moreover, if they contain a carboxylic acid function, the new compoundsof formula I may be converted into the addition salts thereof withinorganic or organic bases, particularly, for pharmaceutical use, intotheir physiologically acceptable addition salts. Suitable bases for thisinclude for example sodium hydroxide, potassium hydroxide, ammonia,cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine andtriethanolamine.

The present invention relates to racemates if the compounds of generalformula I have only one chiral element. However, the application alsoincludes the individual diastereomeric pairs of antipodes or mixturesthereof which are obtained if there is more than one chiral element inthe compounds of general formula I, as well as the individual opticallyactive enantiomers of which the above-mentioned racemates are made up.

Also included in the subject matter of this invention are the compoundsaccording to the invention, including the salts thereof, in which one ormore hydrogen atoms, for example one, two, three, four or five hydrogenatoms, are replaced by deuterium.

The new compounds of general formula I and the physiologicallyacceptable salts thereof have valuable pharmacological properties, basedon their selective CGRP-antagonistic properties. The invention furtherrelates to pharmaceutical compositions containing these compounds, theiruse and the preparation thereof.

The new compounds mentioned above and the physiologically acceptablesalts thereof have CGRP-antagonistic properties and exhibit goodaffinities in CGRP receptor binding studies. The compounds displayCGRP-antagonistic properties in the pharmacological test systemsdescribed hereinafter.

The following experiments were carried out to demonstrate the affinityof the above-mentioned compounds for human CGRP-receptors and theirantagonistic properties:

A. Binding Studies with SK-N-MC Cells (Expressing the Human CGRPReceptor)

SK-N-MC cells are cultivated in “Dulbecco's modified Eagle medium”. Themedium is removed from confluent cultures. The cells are washed twicewith PBS buffer (Gibco 041-04190 M), detached by the addition of PBSbuffer mixed with 0.02% EDTA, and isolated by centrifuging. Afterresuspension in 20 ml of “Balanced Salts Solution” [BSS (in mM): NaCl120, KCl 5.4, NaHCO₃ 16.2, MgSO₄ 0.8, NaHPO₄ 1.0, CaCl₂ 1.8, D-glucose5.5, HEPES 30, pH 7.40] the cells are centrifuged twice at 100×g andresuspended in BSS. After the number of cells has been determined, thecells are homogenised using an Ultra-Turrax and centrifuged for 10minutes at 3000×g. The supernatant is discarded and the pellet isrecentrifuged in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl₂, 1 mMEDTA, pH 7.40) enriched with 1% bovine serum albumin and 0.1%bacitracin, and resuspended (1 ml/1000000 cells). The homogenisedproduct is frozen at −80° C. The membrane preparations are stable formore than 6 weeks under these conditions.

After thawing, the homogenised product is diluted 1:10 with assay buffer(50 mM Tris, 150 mM NaCl, 5 mM MgCl₂, 1 mM EDTA, pH 7.40) andhomogenised for 30 seconds with an Ultra-Turrax. 230 μl of thehomogenised product are incubated for 180 minutes at ambient temperaturewith 50 pM ¹²⁵I-iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham)and increasing concentrations of the test substances in a total volumeof 250 μl. The incubation is ended by rapid filtration throughGF/B-glass fibre filters treated with polyethyleneimine (0.1%) using acell harvester. The protein-bound radioactivity is measured using agamma counter. Non-specific binding is defined as the boundradioactivity after the presence of 1 μM human CGRP-alpha duringincubation.

The concentration binding curves are analysed using computer-aidednon-linear curve fitting.

The compounds mentioned hereinbefore show IC₅₀ values ≧10000 nM in thetest described.

B. CGRP Antagonism in SK-N-MC Cells

SK-N-MC cells (1 million cells) are washed twice with 250 μl incubationbuffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4)and pre-incubated at 37° C. for 15 minutes. After the addition of CGRP(10 μl) as agonist in increasing concentrations (10⁻¹¹ to 10⁻⁶ M), oradditionally the substance in 3 to 4 different concentrations, themixture is incubated for another 15 minutes.

Intracellular cAMP is then extracted by the addition of 20 μl of 1 M HCland centrifugation (2000×g, 4° C., for 15 minutes). The supernatants arefrozen in liquid nitrogen and stored at −20° C.

The cAMP contents of the samples are determined by radioimmunoassay(Messrs. Amersham) and the pA₂ values of antagonistically actingsubstances are determined graphically.

The compounds according to the invention exhibit CGRP-antagonisticproperties in the in vitro test model described, in a dosage rangebetween 10⁻¹² and 10⁻⁵ M.

Indications

In view of their pharmacological properties the compounds according tothe invention and the salts thereof with physiologically acceptableacids are thus suitable for the acute and prophylactic treatment ofheadaches, particularly migraine or cluster headaches and tensionheadaches. Moreover, the compounds according to the invention also havea positive effect on the following diseases: non-insulin-dependentdiabetes mellitus (“NIDDM”), cardiovascular diseases, morphinetolerance, diarrhoea caused by clostridium toxin, skin diseases,particularly thermal and radiation-induced skin damage includingsunburn, lichen, pruritis, pruritic toxidermies and severe itching,inflammatory diseases, e.g. inflammatory diseases of the joints(osteoarthritis, rheumatoid arthritis, neurogenic arthritis),generalised soft-tissue rheumatism (fibromyalgia), neurogenicinflammation of the oral mucosa, inflammatory lung diseases, allergicrhinitis, asthma, COPD, diseases accompanied by excessive vasodilatationand resultant reduced blood supply to the tissues, e.g. shock andsepsis, chronic pain, e.g. diabetic neuropathies, neuropathies inducedby chemotherapy, HIV-induced neuropathies, postherpetic neuropathies,neuropathies induced by tissue trauma, trigeminal neuralgias,temporomandibular dysfunctions, CRPS (complex regional pain syndrome),back pain, and visceral complaints, such as e.g. irritable bowelsyndrome (IBS) and inflammatory bowel syndrome. In addition, thecompounds according to the invention have a general pain-relievingeffect. The symptoms of menopausal hot flushes caused by vasodilatationand increased blood flow in oestrogen-deficient women andhormone-treated patients with prostate carcinoma and castrated men arefavourably affected by the CGRP antagonists of the present applicationin a preventive and acute-therapeutic capacity, this therapeuticapproach being distinguished from hormone replacement by the absence ofside effects.

Preferably, the compounds according to the invention are suitable forthe acute and prophylactic treatment of migraine and cluster headaches,for treating irritable bowel syndrome (IBS) and for the preventive andacute-therapeutic treatment of hot flushes in oestrogen-deficient women.

The dosage required to achieve a corresponding effect is conveniently0.0001 to 3 mg/kg of body weight, preferably 0.01 to 1 mg/kg of bodyweight, when administered intravenously or subcutaneously, and 0.01 to10 mg/kg of body weight, preferably 0.1 to 10 mg/kg of body weight whenadministered orally, nasally or by inhalation, one to three times a dayin each case.

If the treatment with CGRP antagonists and/or CGRP release inhibitors isgiven as a supplement to conventional hormone replacement, it isadvisable to reduce the doses specified above, in which case the dosagemay be from 1/5 of the lower limits mentioned above up to 1/1 of theupper limits specified.

The invention further relates to the use of the compounds according tothe invention as valuable adjuvants for the production and purification(by affinity chromatography) of antibodies as well as in RIA and ELISAassays, after suitable radioactive labelling, for example by tritiationof suitable precursors, for example by catalytic hydrogenation withtritium or replacing halogen atoms with tritium, and as a diagnostic oranalytical adjuvant in neurotransmitter research.

Combinations

Categories of active substance which may be used in combination includee.g. antiemetics, prokinetics, neuroleptics, antidepressants, neurokininantagonists, anticonvulsants, histamine-H1-receptor antagonists,α-blockers, α-agonists and α-antagonists, ergot alkaloids, mildanalgesics, non-steroidal antiphlogistics, corticosteroids, calciumantagonists, 5-HT_(1B/1D)-agonists or other anti-migraine agents whichmay be formulated together with one or more inert conventional carriersand/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene glycol, propylene glycol,cetylstearyl alcohol, carboxymethylcellulose or fatty substances such ashard fat or suitable mixtures thereof, into conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions, solutions, metered dose aerosols or suppositories.

Thus other active substances which may be used for the combinationsmentioned above include for example the non-steroidal antiinflammatoriesaceclofenac, acemetacin, acetylsalicylic acid, acetaminophen(paracetamol), azathioprine, diclofenac, diflunisal, fenbufen,fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen,leflunomide, lornoxicam, mefenamic acid, naproxen, phenylbutazone,piroxicam, sulphasalazine, zomepirac or the pharmaceutically acceptablesalts thereof as well as meloxicam and other selective COX2-inhibitors,such as for example rofecoxib, valdecoxib, parecoxib, etoricoxib andcelecoxib, as well as substances that inhibit earlier or later stages ofprostaglandin synthesis or prostaglandin receptor antagonists such ase.g. EP2-receptor antagonists and IP-receptor antagonists.

It is also possible to use ergotamine, dihydroergotamine,metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine,chlorpromazine, vigabatrin, timolol, isometheptene, pizotifen, botox,gabapentin, pregabalin, duloxetine, topiramate, riboflavin, montelukast,lisinopril, micardis, prochloroperazine, dexamethasone, flunarizine,dextropropoxyphene, meperidine, metoprolol, propranolol, nadolol,atenolol, clonidine, indoramin, carbamazepine, phenytoin, valproate,amitryptiline, imipramine, venlafaxine, lidocaine or diltiazem and other5-HT_(1B/1D)-agonists such as, for example, almotriptan, avitriptan,eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan andzolmitriptan.

Furthermore, CGRP antagonists with vanilloid receptor antagonists, suchas e.g. VR-1 antagonists, glutamate receptor antagonists, such as e.g.mGlu5 receptor antagonists, mGlu1 receptor antagonists, iGlu5 receptorantagonists, AMPA receptor antagonists, purine receptor blockers, suchas e.g. P2X3 antagonists, NO-synthase inhibitors, such as e.g. iNOSinhibitors, calcium channel blockers, such as e.g. PQ-type blockers,N-type blockers, potassium channel openers, such as e.g. KCNQ channelopeners, sodium channel blockers, such as e.g. PN3 channel blockers,NMDA receptor antagonists, acid-sensing ion channel antagonists, such ase.g. ASIC3 antagonists, bradykinin receptor antagonists such as e.g. B1receptor antagonists, cannabinoid receptor agonists, such as e.g. CB2agonists, CB1 agonists, somatostatin receptor agonists, such as e.g.sst2 receptor agonists may be added.

The dosage of these active substances is expediently 1/5 of the lowestusually recommended dose to 1/1 of the normally recommended dose, i.e.for example 20 to 100 mg of sumatriptan.

Formulations

The compounds prepared according to the invention may be administeredeither on their own or optionally in combination with other activesubstances for the treatment of migraine by intravenous, subcutaneous,intramuscular, intraarticular, intrarectal, intranasal route, byinhalation, topically, transdermally or orally, while aerosolformulations are particularly suitable for inhalation. The combinationsmay be administered either simultaneously or sequentially.

Suitable forms for administration are for example tablets, capsules,solutions, syrups, emulsions or inhalable powders or aerosols. Thecontent of the pharmaceutically effective compound(s) in each caseshould be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. %of the total composition, i.e. in amounts which are sufficient toachieve the dosage range specified hereinafter.

The preparations may be administered orally in the form of a tablet, asa powder, as a powder in a capsule (e.g. a hard gelatine capsule), as asolution or suspension. When administered by inhalation the activesubstance combination may be given as a powder, as an aqueous oraqueous-ethanolic solution or using a propellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterised bythe content of one or more compounds of formula I according to thepreferred embodiments above.

It is particularly preferable if the compounds of formula I areadministered orally, and it is also particularly preferable if they areadministered once or twice a day. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample inert diluents such as calcium carbonate, calcium phosphate orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talcand/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules. Suitable suppositories may be made forexample by mixing with carriers provided for this purpose, such asneutral fats or polyethyleneglycol or the derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral administration the tablets may, of course, contain, apart fromthe abovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

It is also preferred if the compounds of formula I are administered byinhalation, particularly preferably if they are administered once ortwice a day. For this purpose, the compounds of formula I have to bemade available in forms suitable for inhalation. Inhalable preparationsinclude inhalable powders, propellant-containing metered-dose aerosolsor propellant-free inhalable solutions, which are optionally present inadmixture with conventional physiologically acceptable excipients.

Within the scope of the present invention, the term propellant-freeinhalable solutions also includes concentrates or sterile ready-to-useinhalable solutions. The preparations which may be used according to theinvention are described in more detail in the next part of thespecification.

Inhalable Powders

If the compounds of formula I are present in admixture withphysiologically acceptable excipients, the following physiologicallyacceptable excipients may be used to prepare the inhalable powdersaccording to the invention: monosaccharides (e.g. glucose or arabinose),disaccharides (e.g. lactose, saccharose, maltose), oligo- andpolysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol,xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures ofthese excipients with one another. Preferably, mono- or disaccharidesare used, while the use of lactose or glucose is preferred,particularly, but not exclusively, in the form of their hydrates. Forthe purposes of the invention, lactose is the particularly preferredexcipient, while lactose monohydrate is most particularly preferred.Methods of preparing the inhalable powders according to the invention bygrinding and micronising and by finally mixing the components togetherare known from the prior art.

Propellant-containing Inhalable Aerosols

The propellant-containing inhalable aerosols which may be used accordingto the invention may contain I dissolved in the propellant gas or indispersed form. The propellant gases which may be used to prepare theinhalation aerosols are known from the prior art. Suitable propellantgases are selected from among hydrocarbons such as n-propane, n-butaneor isobutane and halohydrocarbons such as preferably fluorinatedderivatives of methane, ethane, propane, butane, cyclopropane orcyclobutane. The propellant gases mentioned above may be used on theirown or in mixtures thereof. Particularly preferred propellant gases arefluorinated alkane derivatives selected from TG134a(1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane)and mixtures thereof. The propellant-driven inhalation aerosols usedwithin the scope of the use according to the invention may also containother ingredients such as co-solvents, stabilisers, surfactants,antioxidants, lubricants and pH adjusters. All these ingredients areknown in the art.

Propellant-free Inhalable Solutions

The compounds of formula I are preferably used according to theinvention to prepare propellant-free inhalable solutions and inhalablesuspensions. Solvents used for this purpose include aqueous oralcoholic, preferably ethanolic solutions. The solvent may be water onits own or a mixture of water and ethanol. The solutions or suspensionsare adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids.The pH may be adjusted using acids selected from inorganic or organicacids. Examples of particularly suitable inorganic acids includehydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/orphosphoric acid. Examples of particularly suitable organic acids includeascorbic acid, citric acid, malic acid, tartaric acid, maleic acid,succinic acid, fumaric acid, acetic acid, formic acid and/or propionicacid etc. Preferred inorganic acids are hydrochloric and sulphuricacids. It is also possible to use the acids which have already formed anacid addition salt with one of the active substances. Of the organicacids, ascorbic acid, fumaric acid and citric acid are preferred. Ifdesired, mixtures of the above acids may also be used, particularly inthe case of acids which have other properties in addition to theiracidifying qualities, e.g. as flavourings, antioxidants or complexingagents, such as citric acid or ascorbic acid, for example. According tothe invention, it is particularly preferred to use hydrochloric acid toadjust the pH.

Co-solvents and/or other excipients may be added to the propellant-freeinhalable solutions used for the purpose according to the invention.Preferred co-solvents are those which contain hydroxyl groups or otherpolar groups, e.g. alcohols—particularly isopropyl alcohol,glycols—particularly propyleneglycol, polyethyleneglycol,polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols andpolyoxyethylene fatty acid esters. The terms excipients and additives inthis context denote any pharmacologically acceptable substance which isnot an active substance but which can be formulated with the activesubstance or substances in the pharmacologically suitable solvent inorder to improve the qualitative properties of the active substanceformulation. Preferably, these substances have no pharmacological effector, in connection with the desired therapy, no appreciable or at leastno undesirable pharmacological effect. The excipients and additivesinclude, for example, surfactants such as soya lecithin, oleic acid,sorbitan esters, such as polysorbates, polyvinylpyrrolidone, otherstabilisers, complexing agents, antioxidants and/or preservatives whichguarantee or prolong the shelf life of the finished pharmaceuticalformulation, flavourings, vitamins and/or other additives known in theart. The additives also include pharmacologically acceptable salts suchas, for example, sodium chloride as isotonic agents. The preferredexcipients include antioxidants such as ascorbic acid, for example,provided that it has not already been used to adjust the pH, vitamin A,vitamin E, tocopherols and similar vitamins or provitamins occurring inthe human body. Preservatives may be used to protect the formulationfrom contamination with pathogens. Suitable preservatives are thosewhich are known in the art, particularly cetyl pyridinium chloride,benzalkonium chloride or benzoic acid or benzoates such as sodiumbenzoate in the concentration known from the prior art.

Experimental Section

As a rule IR, ¹H-NMR and mass spectra have been obtained for thecompounds prepared. Unless stated otherwise, R_(f) values are determinedusing ready-made TLC silica gel plates 60 F254 (E. Merck, Darmstadt,Item no. 1.05714) without chamber saturation.

The R_(f) values determined under the heading Polygram-Alox are obtainedusing ready-made Polygram Alox N/UV₂₅₄ TLC films (coated with 0.2 mmaluminium oxide) made by Macherey-Nagel (Düren, Item no. 802 021). Theratios given for the eluants relate to units by volume of the particularsolvents. The units by volume given for NH₃ relate to a concentratedsolution of NH₃ in water.

Unless stated otherwise, the acid, base and salt solutions used inworking up the reaction solutions are aqueous systems of the specifiedconcentrations. Silica gel made by Millipore (MATREX™, 35-70 μm) is usedfor chromatographic purifications.

Aluminium oxide (Alox) made by ICN Biomedicals (Eschwege, Item no.02090) is used for chromatographic purifications. The required activitystage is obtained before use in accordance with the manufacturer'sinstructions.

The HPLC data provided are measured under the parameters listed below:

Method A:

percent by volume of percent by volume of water acetonitrile time (min)(with 0.1% formic acid) (with 0.1% formic acid) 0 95 5 9 10 90 10 10 9011 95 5

Analytical column: Zorbax column (Agilent Technologies), SB (StableBond) C18; 3.5 μm; 4.6×75 mm; column temperature: 30° C.; flow: 0.8mL/min; injection volume: 5 μL; detection at 254 nm

Method B:

percent by volume of percent by volume of water acetonitrile time (min)(with 0.1% formic acid) (with 0.1% formic acid) 0 95 5 4.5 10 90 5 10 905.5 90 10

Analytical column: Zorbax column (Agilent Technologies), SB (StableBond) C18; 3.5 μm; 4.6×75 mm; column temperature: 30° C.; flow: 1.6mL/min; injection volume: 5 μL; detection at 254 nm

Methhod C:

percent by volume of percent by volume of water acetonitrile time (min)(with 0.1% formic acid) (with 0.1% formic acid) 0 95 5 4 50 50 4.5 10 905 10 90 5.5 90 10

Analytical column: Zorbax column (Agilent Technologies), SB (StableBond) C18; 3.5 μm; 4.6×75 mm; column temperature: 30° C.; flow: 1.6mL/min; injection volume: 5 μL; detection at 254 nm

Method D:

percent by volume of percent by volume of water acetonitrile time (min)(with 0.04% TFA) (with 0.04% TFA) 0 80 20 15 20 80 17 20 80

Analytical column: Symmetry C8 Waters—4.6×150 mm; 5 micron, flow: 1.3ml/min, column temperature: 25° C., detection at 254 nm.

In preparative HPLC purifications as a rule the same gradients are usedas were used to obtain the analytical HPLC data.

The products are collected under mass control, the fractions containingproduct are combined and freeze-dried.

In the absence of any more information regarding the configuration, itis unclear whether there are pure enantiomers involved or whetherpartial or even total racemisation has taken place.

The following abbreviations are used in the test descriptions:

Cyc cyclohexane DCM dichloromethane DIPE diisopropylether DMFN,N-dimethylformamide EtOAc ethyl acetate EtOH ethanol HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate AcOH acetic acid i.vac. in vacuo (under vacuum)MCPBA m-chloroperbenzoic acid MeOH methanol NaOAc sodium acetate PEpetroleum ether RT room temperature TBME tert-butylmethylether TBTUO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium- tetrafluoroborateTFA trifluoroacetic acid THF tetrahydrofuranAmine A1[1,4′]bipiperidinyl-4-carbonitrile

A1a) tert. butyl 4-cyano-[1,4′]bipiperidinyl-1′-carboxylate

6.09 g (27.3 mmol) of NaBH(OAc)₃ were added batchwise to a suspension,cooled to 0° C., of 5.44 g (27.3 mmol) tert. butyl4-oxo-piperidin-1-carboxylate, 3.00 g (27.2 mmol) 4-cyanopiperidine and1.6 mL (28.0 mmol) AcOH in 400 mL DCM and the reaction mixture wasstirred overnight, while warming up to RT. 400 mL water were added andthe mixture was acidified with citric acid. The organic phase wasseparated off, the aqueous phase was made alkaline with saturated NaHCO₃solution and extracted exhaustively with DCM. The combined organicphases were concentrated by evaporation i. vac. and the residue wascrystallised with a little DIPE.

Yield: 7.1 g (89% of theory)

ESI-MS: (M+H)⁺=294

A1b) [1,4′]bipiperidinyl-4-carbonitrile

10 mL TFA were added to a suspension of 7.1 g (24.2 mmol) tert. butyl4-cyano-[1,4′]bipiperidinyl-1′-carboxylate in 100 mL DCM and thereaction mixture was stirred overnight at RT. The mixture was evaporateddown i.vac., the residue was taken up in a little EtOH and combined withethereal HCl. The precipitated salt was filtered off and dried. Theproduct was obtained as the bis-hydrochloride salt.

Yield: 3.6 g (56% of theory)

ESI-MS: (M+H)⁺=194

Amine A2

[1,4′]bipiperidinyl-4-yl acetate

A2a) 1′-benzyl-[1,4′]bipiperidinyl-4-ol

25.7 mL (87.4 mmol) titanium(IV)-isopropoxide were added dropwise to amixture of 15.0 mL (79.3 mmol) 1-benzyl-piperidin-4-one and 8.0 g (79.3mmol) 4-hydroxy-piperidine and the reaction mixture was stirred for 2 hat RT. It was diluted with 150 mL EtOH and NaBH₃CN was added batchwise.After the addition had ended the reaction mixture was stirred for 70 hat RT. 60 mL water were added, insoluble constituents were filtered offthrough Celite and the filtrate was evaporated down i.vac. Furtherpurification was carried out by chromatography (silica gel, DCM/MeOH/NH₃80:20:1).

Yield: 17.1 g (79% of theory)

ESI-MS: (M+H)⁺=275

R_(f)=0.51 (silica gel, DCM/MeOH/NH₃ 80:20:1)

A2b) 1′-benzyl-[1,4′]bipiperidinyl-4-yl acetate

A solution of 1.5 g (5.47 mmol) 1′-benzyl-[1,4′]bipiperidinyl-4-ol in 30mL acetic anhydride was heated to 50° C. (bath temperature) for 1 h. Themixture was evaporated down i.vac. and the residue was purified bychromatography (silica gel, EtOAc/MeOH/NH₃ 95:5:0.5).

Yield: 1.46 g (84% of theory)

ESI-MS: (M+H)⁺=317

R_(f)=0.43 (silica gel, EtOAc/MeOH/NH₃ 90:10:1)

A2c) [1,4′]bipiperidinyl-4-yl acetate

A suspension of 1.4 g (4.42 mmol)1′-benzyl-[1,4′]bipiperidinyl-4-yl-acetate and 200 mg 10% Pd/C in 20 mLMeOH was hydrogenated at 3 bar hydrogen pressure for 8 h at RT and for 3h at 40° C. Then another 200 mg of 10% Pd/C were added and the reactionmixture was hydrogenated for a further 6 h. To complete the reaction 200mg Pd(OH)₂ was added and the mixture was hydrogenated for another 12 h.The catalyst was removed by suction filtering and the filtrate wasevaporated down. The product was obtained as a viscous oil.

Yield: 1.00 g (100% of theory)

ESI-MS: (M+H)⁺=227

Retention time (HPLC-MS): 0.5 min (method B)

Amine A3

4-methoxy-[1,4′]bipiperidinyl

A3a) 1′-benzyl-4-methoxy-[1,4′]bipiperidinyl

Under a nitrogen atmosphere 2.4 mL (43.4 mmol) AcOH was added to asolution, cooled to 0° C., of 5.00 g (43.4 mmol) 4-methoxy-piperidineand 9.30 mL (52.1 mmol) 1-benzyl-piperidin-4-one in 200 mL DCM, thereaction mixture was stirred for 2 h at this temperature and thencombined batchwise with 19.3 g (91.2 mmol) NaBH(OAc)₃. After theaddition had ended the mixture was stirred overnight at RT, the reactionsolution was made alkaline with 30% K₂CO₃ solution and combined with 200mL DCM. The organic phase was separated off, washed with 15% K₂CO₃solution and evaporated down i.vac. The oily residue was acidified withmethanolic HCl (1.25 M), concentrated by evaporation i. vac., theresidue was taken up in EtOH, the precipitated product was suctionfiltered, triturated with PE, filtered and dried. The product wasobtained as the bis-hydrochloride salt.

Yield: 2.1 g (13% of theory)

A3b) 4-methoxy-[1,4′]bipiperidinyl

A suspension of 2.1 (5.87 mmol) 1′-benzyl-4-methoxy-[1,4′]bipiperidinyland 1.0 g 10% Pd/C in 50 mL MeOH and 20 mL water was hydrogenated for 8h at RT and 3 bar hydrogen pressure. The catalyst was removed by suctionfiltering, the filtrate was concentrated by evaporation i. vac., theresidue was triturated with diethyl ether, suction filtered and dried.

Yield: 1.50 g (94% of theory)

ESI-MS: (M+H)⁺=199

Amine A4

1-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-piperazine

A4a) 1,1-dioxo-tetrahydro-1λ⁶-thiopyran-4-one

A solution of 5.3 g (45.6 mmol) tetrahydrothiopyran-4-one in 50 mL EtOAcwas heated to 50° C. At this temperature, 18.6 mL (110 mmol) peraceticacid solution (39% in AcOH) were slowly added dropwise, while thetemperature was kept between 50-55° C. using an ice bath. After theaddition had ended the reaction mixture was cooled to RT, during whichtime a precipitate was formed. This was suction filtered and dried. Theproduct was reacted further without purification.

Yield: 6.70 g (99% of theory, purity 80%) EI-MS: (M)⁺=148

R_(f)=0.50 (silica gel, EtOAc)

A4b) 1-benzyl-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-piperazine

A suspension of 5.1 g (27.5 mmol, purity 80%)1,1-dioxo-tetrahydro-1λ⁶-thiopyran-4-one, 7.0 mL (40.3 mmol)1-benzyl-piperazine and 30 g molecular sieve A3 in 140 mL isopropanolwas combined with a spatula tip of p-toluenesulphonic acid and refluxedfor 7 h. The molecular sieve was filtered off, the reaction solution wascombined with 8.0 g (37.7 mmol) NaBH(OAc)₃ and stirred overnight at RT.1 g NaBH₄ was added to the reaction solution, the mixture was heated to60° C. for 2 h, mixed with water and then filtered. The filtrate wasacidified with 4 M HCl, freed from the isopropanol i.vac., made alkalinewith saturated NaHCO₃ solution and extracted exhaustively with EtOAc.The combined organic phases were dried on Na₂SO₄, filtered andconcentrated by evaporation i. vac. The residue was purified bychromatography (Alox, activity stage II-III, EtOAc).

Yield: 0.64 g (7% of theory)

ESI-MS: (M+H)⁺=309

R_(f)=0.50 (Polygram-Alox, EtOAc)

A4c) 1-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-piperazine

A suspension of 0.57 g (1.85 mmol)1-benzyl-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-piperazine and 300mg 10% Pd/C in 30 mL MeOH was hydrogenated at 50° C. and 50 psi hydrogenpressure for 10 h. The catalyst was removed by suction filtering and thefiltrate was concentrated by evaporation i. vac. The product was reactedfurther without purification.

Yield: 0.38 g (94% of theory)

ESI-MS: (M+H)⁺=219

Amine A5

1-methyl-4-(4-methyl-piperidin-4-yl)-piperazine

A5a) 1-benzyl-4-(4-methyl-piperazin-1-yl)-piperidine-4-carbonitrile

A solution of 10.0 g (45.3 mmol)1-benzyl-4-hydroxy-piperidin-4-carbonitrile and 6.0 mL (53.6 mmol)N-methyl-piperazine in 50 mL MeOH was refluxed for 6 h. The mixture wasevaporated down i.vac. to about 25 mL, during which time a precipitatewas formed. 50 mL of ice water was added, the precipitate was filteredoff and dried at 40° C.

Yield: 11.5 g (85% of theory)

ESI-MS: (M+H)⁺=299

R_(f)=0.58 (Polygram-Alox, PE/EtOAc 1:1)

A5b) 1-(1-benzyl-4-methyl-piperidin-4-yl)-4-methyl-piperazine

10 mL methylmagnesium chloride solution (30 mmol, 3 M in THF) were addedat RT to a solution of 3.0 g (10.1 mmol)1-benzyl-4-(4-methyl-piperazin-1-yl)-piperidin-4-carbonitrile in 50 mLdry THF and the reaction mixture was stirred for 2 h. It was combinedwith saturated NH₄Cl solution, stirred for 10 min, extractedexhaustively with diethyl ether and the combined organic phases weredried on Na₂SO₄. After the elimination of the desiccant and solvent theresidue was purified by chromatography (Alox, activity stage II-III,gradient DCM/MeOH 100:1 to 50:1).

Yield: 1.01 g (33% of theory)

ESI-MS: (M+H)⁺=288

A5c) 1-methyl-4-(4-methyl-piperidin-4-yl)-piperazine

A suspension of 0.99 g (3.27 mmol)1-(1-benzyl-4-methyl-piperidin-4-yl)-4-methyl-piperazine and 200 mg 10%Pd/C in 25 mL MeOH was hydrogenated at 50° C. and 50 psi hydrogenpressure for 2 h. To complete the reaction a further 200 mg catalystwere added and the reaction mixture was hydrogenated for a further 22 hat 60° C. and 50 psi hydrogen pressure. The catalyst was filtered offand the filtrate evaporated to dryness. The product was reacted furtherwithout purification.

Yield: 0.56 g (87% of theory)

ESI-MS: (M+H)⁺=198

Amine A6

4-(4-methyl-piperidin-4-yl)-morpholine

A6a) 1-benzyl-4-morpholin-4-yl-piperidin-4-carbonitrile

A solution of 5.25 g (23.8 mmol)1-benzyl-4-hydroxy-piperidine-4-carbonitrile and 2.2 mL (25.2 mmol)morpholine in 30 mL MeOH was refluxed for 6 h. The mixture wasevaporated to dryness i. vac., while the product was obtained in theform of crystals.

Yield: 6.9 g (100% of theory)

ESI-MS: (M+H)⁺=286

A6b) 4-(1-benzyl-4-methyl-piperidin-4-yl)-morpholine

Prepared analogously to Example A5b from 6.88 g (23.6 mmol)1-benzyl-4-morpholin-4-yl-piperidin-4-carbonitrile and 25 mL methylmagnesium chloride solution (75 mmol, 3 M in THF).

Yield: 3.0 g (44% of theory)

ESI-MS: (M+H)⁺=275

R_(f)=0.6 (Polygram-Alox, DCM/MeOH 50:1)

A6c) 4-(4-methyl-piperidin-4-yl)-morpholine

A suspension of 3.0 g (10.4 mmol)4-(1-benzyl-4-methyl-piperidin-4-yl)-morpholine and 150 mg 10% Pd/C in50 mL MeOH was hydrogenated at 50° C. and 50 psi hydrogen pressure for 2h. 1 mL concentrated HCl was added and the mixture was hydrogenated fora further 18 h at 50° C. and 50 psi hydrogen pressure. The catalyst wasfiltered off and the filtrate was evaporated to dryness. The product,which was obtained as the hydrochloride salt, was reacted furtherwithout purification.

Yield: 2.4 g (94% of theory)

ESI-MS: (M+H)⁺=185

Amine 7

Ethyl 3-[4,4′]bipiperidinyl-1-yl-propionate

A7a) tert.butyl1′-(2-ethoxycarbonyl-ethyl)-[4,4′]bipiperidinyl-1-carboxylate

4.4 mL (40.6 mmol) ethyl acrylate were added to a solution of 10.0 g(37.3 mmol) tert. butyl [4,4′]bipiperidinyl-1-carboxylate in 100 mL EtOHand the reaction mixture was refluxed for 2 h. To complete the reactiona further 1 mL (9.2 mmol) ethyl acrylate were added, the mixture wasrefluxed for 1 h and left overnight at RT. The solvent was eliminated i.vac. and the crude product was further reacted without any purification.

Yield: 14.0 g (100% of theory)

ESI-MS: (M+H)⁺=369

A7b) ethyl 3-[4,4′]bipiperidinyl-1-yl-propionate

28 mL TFA were added dropwise to a solution of 14.0 g of the crudeproduct of Example A7a in 250 mL DCM and the reaction mixture wasstirred for 4 h at RT. The mixture was evaporated down i.vac., theresidue was taken up in 200 mL DCM and this solution was added batchwiseto a solution of 20 g Na₂CO₃ in 120 mL water. The organic phase wasseparated off, the aqueous phase was extracted twice more with DCM andthe combined organic phases were dried on Na₂SO₄. After the eliminationof the desiccant and solvent the residue was dried and reacted withoutfurther purification.

Yield: 8.8 g (88% of theory)

ESI-MS: (M+H)⁺=269

Amine A8

Ethyl 3-[1,4′]bipiperidinyl-4-yl-propionate

A8a) tert. butyl4-(2-methoxycarbonyl-ethyl)-[1,4′]bipiperidinyl-1′-carboxylate

A solution of 4.00 g (19.3 mmol) methyl 3-piperidin-4-yl-propionate(used as the hydrochloride salt) and 3.85 g (19.3 mmol) tert. butyl4-oxo-piperidine-1-carboxylate in 50 mL THF was adjusted to pH 5 withAcOH and the reaction mixture was stirred for 1 h at RT. 5.15 g (24.3mmol) NaBH(OAc)₃ were added batchwise while being cooled and thereaction solution was stirred overnight at RT. 90 mL 30% K₂CO₃ solutionwere added dropwise, the mixture was extracted exhaustively with EtOAcand the combined organic phases were dried on Na₂SO₄. After theelimination of the desiccant and solvent the product was reacted furtherwithout any purification.

Yield: 5.4 g (79% of theory)

ESI-MS: (M+H)⁺=355

R_(f)=0.63 (silica gel, DCM/MeOH/NH₃ 80:20:2)

A8b) ethyl 3-[1,4′]bipiperidinyl-4-yl-propionate

A solution of 5.4 g (15.2 mmol) tert. butyl4-(2-methoxycarbonyl-ethyl)-[1,4′]bipiperidinyl-1′-carboxylate in 150 mLethanolic HCl (1.25 M) was stirred overnight at RT. The solvent waslargely eliminated i.vac., the precipitate formed was suction filteredand dried. The product, which was obtained as the bis-hydrochloridesalt, was reacted further without purification.

Yield: 2.3 g (44% of theory)

ESI-MS: (M+H)⁺=269

Retention time (HPLC-MS): 1.2 min (method B)

Amine A9

Ethyl 4-(4-piperazin-1-yl-piperidin-1-yl)-butanoate

A9a) ethyl 4-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-butanoate

A solution of 3.11 g (12.0 mmol) 1-benzyl-4-piperidin-4-yl-piperazineand 7.5 mL (12.0 mmol, 15% in water) 4-oxo-butanoic acid in 70 mL THFwas adjusted to pH with AcOH and stirred for 1 h at RT. While coolingwith ice, 5.35 g (24.0 mmol) NaBH(OAc)₃ were added batchwise and themixture was then stirred overnight at RT. 80 mL of 30% K₂CO₃ solutionwere added dropwise to the reaction mixture within 15 min and after theaddition had ended this mixture was washed twice with EtOAc. The aqueousphase was evaporated down by half i.vac., neutralised with 1 M KHSO₄solution, the precipitate formed was suction filtered, the filtrate waswashed again with EtOAc and the aqueous phase was concentrated byevaporation i. vac. 150 mL of ethanolic HCl (1.25 M) was added and themixture was stirred overnight at RT. The mixture was evaporated downi.vac., the residue was taken up in a little 15% K₂CO₃ solution,extracted exhaustively with EtOAc and the combined organic phases weredried on Na₂SO₄. After the elimination of the desiccant and solvent theresidue was reacted further without any purification.

Yield: 2.9 g (65% of theory)

ESI-MS: (M+H)⁺=374

A9b) ethyl 4-(4-piperazin-1-yl-piperidin-1-yl)-butanoate

A suspension of 2.9 g (7.76 mmol) ethyl4-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-butanoate and 300 mg 10%Pd/C in 60 mL MeOH was hydrogenated at RT and 50 psi hydrogen pressurefor 24 h. The catalyst was filtered off, the mixture was evaporated downi.vac., the residue was taken up in a little DIPE and isopropanol andcombined with 4 M HCl in 1,4-dioxane. The precipitated bis-hydrochloridesalt was separated off and dried.

Yield: 2.5 g (90% of theory)

ESI-MS: (M+H)⁺=284

Retention time (HPLC-MS): 0.7 min (method B)

Amine A10

Ethyl 3-(4-piperazin-1-yl-piperidin-1-yl)-propionate

A10a) ethyl 3-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-propionate

5.5 mL (50.8 mmol) ethyl acrylate were added to a solution of 11.7 g(44.9 mmol) 1-benzyl-4-piperidin-4-yl-piperazine in 120 mL dry EtOH andthe reaction mixture was refluxed for 1 h and then stirred overnight atRT. The solvent was eliminated i.vac. and the residue was dried for 1 hunder an oil pump vacuum. The crude product was reacted further withoutpurification.

Yield: 16.5 g (99% of theory)

ESI-MS: (M+H)⁺=360

A10b) ethyl 3-(4-piperazin-1-yl-piperidin-1-yl)-propionate

A suspension of 16.5 g of the crude product from Example A10a and 1.6 g10% Pd/C in 200 mL EtOH and was hydrogenated for 4 h at 50° C. and 50psi hydrogen pressure. The catalyst was removed by suction filtering,the filtrate was evaporated down to about 120 mL and combined with 72 mLethanolic HCl (1.3 M). The precipitate formed was suction filtered anddried i. vac.

The product was obtained as the bis-hydrochloride salt.

Yield: 12.6 g (83% of theory)

ESI-MS: (M+H)⁺=270

Amine A11

Ethyl 3-(4-piperidin-4-yl-piperazin-1-yl)-propionate

A11a) ethyl 3-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-propionate

12.5 mL (73.0 mmol) ethyldiisopropylamine and 5.0 mL (46.1 mmol) ethylacrylate were added to a solution of 11.0 g (33.2 mmol)1-(1-benzyl-piperidin-4-yl)-piperazine (used as the bis-hydrochloridesalt) in 40 mL EtOH and the reaction mixture was heated to 90° C. (bathtemperature) for 3 h. After cooling the mixture was combined with water,extracted exhaustively with EtOAc and the combined organic phases weredried on Na₂SO₄. After the elimination of the desiccant and solvent theresidue was purified by chromatography (silica gel, DCM/EtOH/NH₃100:10:1).

Yield: 6.8 g (56% of theory)

ESI-MS: (M+H)⁺=360

R_(f)=0.64 (silica gel, DCM/MeOH/NH₃90:9:1)

A11b) ethyl 3-(4-piperidin-4-yl-piperazin-1-yl)-propionate

A suspension of 5.13 g (14.3 mmol) ethyl3-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-propionate and 1.0 g 10%Pd/C in 100 mL EtOH was hydrogenated for 2 h at 50° C. and 50 psihydrogen pressure. The catalyst was filtered off and the filtrate wasevaporated to dryness. The oily product was reacted further withoutpurification.

Yield: 3.6 g (93% of theory)

ESI-MS: (M+H)⁺=270

Amine A12

Ethyl ([1,4′]bipiperidinyl-4-yloxy)-acetate

A12a) benzyl4-tert-butoxycarbonylmethoxy-[1,4′]bipiperidinyl-1′-carboxylate

2.90 g (13.3 mmol) NaBH(OAc)₃ were added batchwise to a solution of 2.58g (11.1 mmol)) tert. butyl 4-oxo-piperidine-1-carboxylate and 2.80 g(12.4 mmol) tert. butyl (piperidin-4-yloxy)-acetate in 30 mL THF and thereaction mixture was stirred overnight at RT. 50 mL of 1 M NaOH wasadded, the mixture was stirred for 1 h at RT, extracted exhaustivelywith EtOAc and the combined organic phases were dried on Na₂SO₄. Afterthe elimination of the desiccant and solvent the residue was purified bychromatography (Alox, activity stage II-III, DCM/MeOH 100:1).

Yield: 3.1 g (65% of theory)

ESI-MS: (M+H)⁺=433

A12b) tert. butyl ([1,4′]bipiperidinyl-4-yloxy)-acetate

A suspension of 3.08 g (7.12 mmol) of benzyl4-tert-butoxycarbonylmethoxy-[1,4′]bipiperidinyl-1′-carboxylate and 300mg of 10% Pd/C in 60 mL MeOH was hydrogenated at 50° C. and 50 psihydrogen pressure for 2 h. The catalyst was removed by suction filteringand the filtrate was evaporated to dryness. The oil remaining wasreacted further without purification.

Yield: 2.15 g (99% of theory)

ESI-MS: (M+H)⁺=299

A12c) ethyl ([1,4′]bipiperidinyl-4-yloxy)-acetate

A solution of 100 mg (0.33 mmol) tert. butyl([1,4′]bipiperidinyl-4-yloxy)-acetate in 1 mL EtOH was combined with 2mL ethanolic HCl with heating, the mixture was refluxed for a further 2h and left overnight at RT. The precipitate formed was suction filteredand dried.

Yield: 71 mg (63% of theory)

ESI-MS: (M+H)⁺=271

EXAMPLE 1 (R)-1-heptylcarbamoyl-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

1a) 2-benzyloxy-5-bromo-1,3-dimethylbenzene

39.9 g (286 mmol) K₂CO₃ were added to a solution of 50.0 g (249 mmol)2,6-dimethyl-4-bromophenol in 500 mL DMF and the mixture was stirred for20 min. Then 34.0 mL (286 mmol) benzyl chloride were slowly addeddropwise and the reaction mixture was stirred for 3 h at 100° C. bathtemperature. After the reaction had ended the mixture was poured onto500 mL water and extracted exhaustively with EtOAc. The organic phaseswere combined, dried on Na₂SO₄ and concentrated by evaporation i. vac.

Yield: quantitative

GC-MS: (M⁺)=290/292 (Br)

R_(f)=0.87 (silica gel, Cyc/EtOAc 3:1)

1b) methyl 2-acetylamino-3-(4-benzyloxy-3,5-dimethyl-phenyl)-acrylate

Under a nitrogen atmosphere a mixture of 40.0 g (137 mmol)2-benzyloxy-5-bromo-1,3-dimethylbenzene and 24.1 g (165 mmol) methyl2-acetylamino-acrylate in 420 mL triethylamine and 200 mL acetonitrilewas combined with 3.5 g (11.2 mmol) tri-o-tolyl-phosphane and 2.5 g(11.1 mmol) Pd(OAc)₂ and stirred for 18 h at 80° C. The precipitate wassuction filtered, the filtrate concentrated by evaporation i. vac. andcombined with 800 mL DCM and 800 mL water. The organic phase wasseparated off, suction filtered on Na₂SO₄, the solvent was eliminated i.vac., the residue was stirred with EtOAc, suction filtered and dried i.vac.

Yield: 31.1 g (64% of theory)

ESI-MS: (M+H)⁺=354

Retention time (HPLC-MS): 8.6 min (method A)

1c) 3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-oxo-propionic acid

31.1 g (88.1 mmol) methyl2-acetylamino-3-(4-benzyloxy-3,5-dimethyl-phenyl)-acrylate in 150 mL1,4-dioxane were combined with 125 mL 4 M HCl, refluxed for 7 h andstirred overnight at RT. The precipitate was suction filtered, washedwith water and dried at 45° C. in the vacuum drying cupboard.

Yield: 14.3 g (54% of theory)

EI-MS: (M)⁺=298

Retention time (HPLC-MS): 9.0 min (method A)

1d) (R)-3-(4-benzoyl-3,5-dimethyl-phenyl)-2-hydroxy-propionic acid

Under a nitrogen atmosphere a solution of 14.3 g (47.8 mmol)3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-oxo-propionic acid and 8.3 mL(59.8 mmol) triethylamine in 170 mL THF at −35° C. was combined with asolution of 22.1 (69.0 mmol) (1R)-B-chlorodiisopinocampheylborane in 70mL THF within 30 min. After the addition had ended the cooling bath wasremoved and the reaction solution was stirred overnight at RT. Thereaction mixture was made alkaline at 0° C. with 70 mL 1 M NaOH,combined with 100 mL TBME, stirred for 15 min and the phases wereseparated. The organic phase was washed with 50 mL water and three timeswith 50 mL of 1 M NaOH. The combined aqueous phases were acidified withsemiconcentrated HCl, extracted exhaustively with EtOAc and the combinedorganic phases were dried on Na₂SO₄. After the elimination of thedesiccant and solvent the residue was reacted further without anypurification.

Yield: 14.0 g (98% of theory)

ESI-MS: (M−H)⁻=299

Retention time (HPLC-MS): 7.9 min (method A)

1e) methyl (R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-hydroxy-propionate

2.0 mL (27.4 mmol) SOCl₂ were added dropwise to a solution, cooled to 0°C., of 14.0 g (23.3 mmol)(R)-3-(4-benzoyl-3,5-dimethyl-phenyl)-2-hydroxy-propionic acid in 150 mLMeOH and the reaction mixture was stirred for 1 h at RT. The reactionsolution was concentrated by evaporation i. vac. and the residue waspurified by chromatography (silica gel, Cyc/EtOAc 3:1).

Yield: 5.7 g (78% of theory)

ESI-MS: (M+NH₄)⁺=332

Retention time (HPLC-MS): 9.1 min (method A)

1f) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Under a nitrogen atmosphere 1.93 g (9.58 mmol) 4-nitrophenylchloroformate was added to a solution of 1.17 g (9.58 mmol)4-dimethylaminopyridine in 50 mL pyridine, the mixture was stirred for1.5 h at RT, combined with 3.0 g (9.58 mmol) methyl(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-hydroxy-propionate and themixture was stirred for 20 min at RT. Then 2.35 g (9.58 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were addedand the mixture was stirred for 20 h at RT. The reaction mixture wasconcentrated by evaporation i. vac., the residue was taken up in EtOAc,the organic phase was washed with 10% KHSO₄ and saturated NaHCO₃solution and dried on Na₂SO₄. After the elimination of the desiccant andsolvent the residue was purified by chromatography (silica gel, gradientCyc/EtOAc 1:1 to 1:2).

Yield: 3.21 g (57% of theory)

ESI-MS: (M+H)⁺=586

Retention time (HPLC-MS): 10.4 min (method A)

1g) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 3.21 g (5.48 mmol)(R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-methoxy-carbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 80 mL THF was combined with a solution of 200 mg (8.35 mmol) LiOH in40 mL water and the mixture was stirred for 1 h at RT. The reactionmixture was concentrated by evaporation i. vac., the residue was takenup in 100 mL water, acidified with 2 M HCl, the precipitate was suctionfiltered and dried in the vacuum drying cupboard at 40° C.

Yield: quantitative

ESI-MS: (M+H)⁺=572

Retention time (HPLC-MS): 9.2 min (method A)

1h) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

3.72 g (6.51 mmol)(R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 50 mL DCM were combined with 300 mg of 10% Pd/C and shaken at RT and3 bar hydrogen until the reaction came to an end. The catalyst wasremoved by suction filtering and the solvent was concentrated byevaporation i. vac. The residue was triturated with DIPE and suctionfiltered.

Yield: 2.41 g (77% of theory)

ESI-MS: (M+H)⁺=482

Retention time (HPLC-MS): 7.0 min (method A)

1i) (R)-1-heptylcarbamoyl-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 100 mg (0.21 mmol)(R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,73 mg (0.23 mmol) TBTU and 36 μL (0.18 mmol) triethylamine in 1 mL DMFwas stirred for 1 h at RT. Then 26 mg (0.23 mmol) n-heptylamine wasadded and the reaction mixture was stirred for 5 h at RT. The reactionsolution was filtered through a syringe filter and purified directly byHPLC without any further working up. The fractions containing theproduct were combined and lyophilised.

Yield: 48 mg (40% of theory)

ESI-MS: (M−H)⁻=577

Retention time (HPLC-MS): 4.6 min (method B)

The following compounds were prepared analogously from in each case 100mg (Examples 1.1 to 1.5) or from in each case 80 mg (Example 1.6 to 1.8)of (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

Example —R³—R⁴ Yield (%) Mass spectrum Retention time HPLC (method) 1.1

27 648 [M + H]⁺ 3.1 min (B) 1.2

13 687 [M + H]⁺ 3.0 min (B) 1.3

52 631 [M + H]⁺ 3.6 min (B) 1.4

19 657 [M + H]⁺ 3.1 min (B) 1.5

46 608 [M + H]⁺ 3.1 min (B) 1.6

44 673 [M + H]⁺ 2.6 min (B) 1.7

42 690 [M + H]⁺ 2.7 min (B) 1.8

59 680 [M + H]⁺ 4.4 min (B)

EXAMPLE 1.9(R)-1-(6-amino-hexylcarbamoyl)-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 55 mg (0.08 mmol)(R)-1-(6-tert-butoxycarbonylamino-hexylcarbamoyl)-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 1.8) in 1 mL of 1M HCl was stirred overnight at RT. Thereaction solution was lyophilised and the residue was purified by HPLC.The fractions containing the product were combined and againlyophilised.

Yield: 4 mg (8% of theory)

ESI-MS: (M+H)⁺=580

Retention time (HPLC-MS): 2.6 min (method B)

EXAMPLE 1.10(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(3,4,5,6-tetrahydro-2H-4,4′-bipyridinyl-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

67 mg (0.42 mmol) 1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl were added atRT to a solution of 182 mg (0.38 mmol)(R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,133 mg (0.42 mmol) TBTU and 66 μL (0.47 mmol) triethylamine in 10 mL THFand 2 mL DMF and the reaction mixture was stirred for 2 h. 20 mL EtOAcwere added, the organic phase was washed with 20 mL semisaturated NaHCO₃solution and dried on Na₂SO₄. After the elimination of the desiccant andsolvent the residue was purified by HPLC. The fractions containing theproduct were combined, evaporated down, the residue was made alkalinewith semisaturated NaHCO₃ solution, extracted with 50 mL EtOAc and theorganic phase was dried on Na₂SO₄. After the elimination of thedesiccant and solvent the residue was stirred with DIPE, suctionfiltered and dried.

Yield: 145 mg (61% of theory)

ESI-MS: (M+H)⁺=626

Retention time (HPLC-MS): 3.1 min (method B)

EXAMPLE 1.11 (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-piperazin-1-yl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

1.11a)(R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 1.54 g (2.69 mmol)(R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 1g), 952 mg (2.96 mmol) TBTU and 0.47 mL (3.37 mmol)triethylamine in 10 mL THF and 2 mL DMF the mixture was stirred for 1 hat RT. Then 0.52 mL (2.96 mmol) 1-benzyl-piperazine was added and thereaction mixture was stirred for another 14 h at RT. 30 mL EtOAc wereadded, the organic phase was washed with semisaturated NaHCO₃ solutionand dried on Na₂SO₄.

After the elimination of the desiccant and solvent the residue waspurified by chromatography (silica gel, EtOAc/Cyc 95:5), the fractionscontaining the product were combined, evaporated down, the residue wastriturated with DIPE, suction filtered and dried.

Yield: 1.62 g (82% of theory)

ESI-MS: (M+H)⁺=730

Retention time (HPLC-MS): 4.3 min (method B)

1.11b)(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-piperazin-1-yl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

1.62 g (2.22 mmol)(R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 40 mL MeOH were combined with 150 mg 10% Pd/C and hydrogenated at RTand 3 bar hydrogen until the reaction came to an end. The catalyst wasremoved by suction filtering and the solvent was concentrated byevaporation i. vac. The residue was purified by chromatography (silicagel, EtOAc/MeOH/NH₃ 85:13.5:1.5).

Yield: 1.03 g (85% of theory)

ESI-MS: (M+H)⁺=550

Retention time (HPLC-MS): 2.7 min (method B)

EXAMPLE 1.12(R)-2-(4-cyclopropylmethyl-piperazin-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 100 mg (0.18 mmol)(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-piperazin-1-yl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,20 μL (0.37 mmol) AcOH and 41.6 μL (0.55 mmol) cyclopropanecarbaldehydein 2 mL THF/MeOH (2:1) was stirred overnight at RT. After cooling to 0°C. the mixture was combined with 24 mg (0.36 mmol) NaBH₃CN, stirred fora further 4 h at this temperature and then overnight at RT. The solventswere eliminated, the residue was taken up in 1 mL DMF and purified byHPLC. The fractions containing the product were combined andlyophilised.

Yield: 45 mg (41% of theory)

ESI-MS: (M+H)⁺=604

Retention time (HPLC-MS): 3.1 min (method B)

The following compounds were prepared analogously from in each case 100mg (R)-1-(4-hydroxy-3,5-dimethyl -benzyl)-2-oxo-2-piperazin-1-yl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of aldehyde or ketone:

Mass Retention time Yield spec- HPLC Example R⁴ (%) trum (method) 1.13

27 650 [M + H]⁺ 3.2 min (B) 1.14

58 675 [M + H]⁺ 2.9 min (B) 1.15

17 620 [M + H]⁺ 3.3 min (B) 1.16

57 632 [M + H]⁺ 3.3 min (B) 1.17

46 660 [M + H]⁺ 3.6 min (B)

EXAMPLE 1.18(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(1′-oxy-3,4,5,6-tetrahydro-2H-4,4′-bipyridinyl-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

77 mg (0.46 mmol) MCPBA were added to a solution, cooled to 0° C., of253 mg (0.40 mmol)(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(3,4,5,6-tetrahydro-2H-4,4′-bipyridinyl-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 1.10) in 10 mL chloroform and the reaction mixture was stirredfor 2 h, during which time it heated up to RT. The mixture wasevaporated down i.vac., the residue was taken up in a little DMF andpurified by HPLC. The fractions containing the product were combined andlyophilised.

Yield: 107 mg (41% of theory)

ESI-MS: (M+H)⁺=642

Retention time (HPLC-MS): 3.4 min (method B)

EXAMPLE 1.19(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(1′-methyl-1′-oxy-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

1.19a)(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 1i from 150 mg (0.31 mmol)(R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 62 mg (0.34 mmol) 1-methyl-[4,4′]bipiperidinyl.

Yield: 42 mg (21% of theory)

ESI-MS: (M+H)⁺=646

Retention time (HPLC-MS): 3.1 min (method B)

1.19b)(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(1′-methyl-1′-oxy-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 1.18 from 40 mg (0.06 mmol)(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(1′-methyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 17 mg (0.07 mmol) MCPBA.

Yield: 17 mg (41% of theory)

ESI-MS: (M+H)⁺=662

Retention time (HPLC-MS): 3.2 min (method B)

EXAMPLE 1.20(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-[4-(4-oxy-morpholin-4-yl)-piperidin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

1.20a)(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 1i from 70 mg (0.15 mmol)(R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 25 mg (0.15 mmol) 4-piperidin-4-yl-morpholine.

Yield: 35 mg (38% of theory)

ESI-MS: (M+H)⁺=634

Retention time (HPLC-MS): 5.6 min (method A)

1.20b)(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-[4-(4-oxy-morpholin-4-yl)-piperidin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 1.18 from 80 mg (0.13 mmol)(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 24 mg (0.14 mmol) MCPBA.

Yield: 36 mg (44% of theory)

ESI-MS: (M+H)⁺=650

Retention time (HPLC-MS): 4.1 min (method C)

EXAMPLE 1.21(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-methoxy-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 1i from 80 mg (0.17 mmol)(R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,77 μL (0.55 mmol) triethylamine and 46 mg (0.17 mmol)4-methoxy-[1,4′]bipiperidinyl (used as the bis-hydrochloride salt).

Yield: 74 mg (67% of theory)

ESI-MS: (M+H)⁺=662

Retention time (HPLC-MS): 6.1 min (method A)

EXAMPLE 1.22(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-[4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-piperidin-1-yl]-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 1.21 from 80 mg (0.17 mmol)(R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,77 μL (0.55 mmol) triethylamine and 47 mg (0.17 mmol)4-piperidin-4-yl-thiomorpholine-1-oxide (used as the bis-hydrochloridesalt).

Yield: 45 mg (41% of theory)

ESI-MS: (M+H)⁺=666

Retention time (HPLC-MS): 5.7 min (method A)

EXAMPLE 1.23(R)-2-[4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

1.23a)(R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-[4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 1i from 150 mg (0.26 mmol)(R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 1g) and 57 mg (0.26 mmol)1-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-piperazine.

Yield: 49 mg (24% of theory)

ESI-MS: (M+H)⁺=772

Retention time (HPLC-MS): 3.9 min (method B)

1.23b)(R)-2-[4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 45 mg (0.06 mmol)(R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-[4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 10 mL MeOH was combined with 10 mg 10% Pd/C and hydrogenated at RTand 3 bar hydrogen pressure until the reaction came to an end. Thecatalyst was removed by suction filtering and the residue was purifiedby HPLC. The fractions containing the product were combined andlyophilised.

Yield: 23 mg (57% of theory)

ESI-MS: (M+H)⁺=682

Retention time (HPLC-MS): 3.1 min (method B)

EXAMPLE 1.24(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-methyl-4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 1i from 80 mg (0.17 mmol)(R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 1h) and 36 mg (0.18 mmol)1-methyl-4-(4-methyl-piperidin-4-yl)-piperazine.

Yield: 36 mg (32% of theory)

ESI-MS: (M+H)⁺=661

Retention time (HPLC-MS): 2.5 min (method B)

EXAMPLE 1.25(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-methyl-4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

55 mg (0.22 mmol) 4-(4-methyl-piperidin-4-yl)-morpholine (used as thehydrochloride salt, purity 90%) were added at RT to a solution of 90 mg(0.19 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 1h), 70 mg (0.22 mmol) TBTU and 70 μL (0.50 mmol) triethylaminein 1 mL DMF and the reaction mixture was stirred for 20 h. The reactionsolution was poured onto saturated NaHCO₃ solution, the precipitateformed was filtered off and dried. Further purification was carried outby HPLC, the fractions containing the product were combined andlyophilised.

Yield: 32 mg (26% of theory)

ESI-MS: (M+H)⁺=648

Retention time (HPLC-MS): 3.0 min (method B)

EXAMPLE 1.26(R)-1-(4-formyloxy-3,5-dimethyl-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 100 μL acetic anhydride and 1 mL formic acid in 3 mL DCMwas stirred for 2 h at RT (formation of the mixed anhydride). Then 100mg (0.16mmol)-(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 1.20a) were added and the reaction mixture was stirred for 2 hat RT. The reaction solution was evaporated down and the residue wasagain added to a solution of the mixed anhydride and stirred overnightat RT. The mixture was evaporated down i.vac. and the residue waspurified by HPLC. The fractions containing the product were combined andlyophilised.

Yield: 77 mg (69% of theory)

ESI-MS: (M+H)⁺=662

Retention time (HPLC-MS): 3.1 min (method B)

EXAMPLE 2(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate

2a) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate

Prepared analogously to Example 1f from 5.0 g (15.9 mmol) methyl(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-hydroxy-propionate (Example1e) and 5.98 g (15.9 mmol)3-5-phenyl-2-piperidin-4-yl-2,4-dihydro-1,2,4-triazol-3-one (purity65%).

Yield: 4.96 g (53% of theory)

ESI-MS: (M+H)⁺=585

Retention time (HPLC-MS): 5.0 min (method B)

2b) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate

A solution of 310 mg (12.93 mmol) LiOH in 30 mL water was added to asolution of 4.96 g (8.48 mmol)(R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-methoxy-carbonyl-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylatein 50 mL THF and the reaction mixture was stirred for 7 h at RT. Thesolution was stored overnight at −18° C. and after heating to RT afurther 310 mg LiOH were added to complete the reaction. After 1 h thereaction solution was concentrated by evaporation i. vac., the residuewas taken up in 150 mL water and acidified with 1 M HCl. The precipitatewas filtered off and dried at 40° C.

Yield: 4.75 g (98% of theory)

ESI-MS: (M+H)⁺=571

Retention time (HPLC-MS): 4.3 min (method B)

2c) (R)-1-carboxy-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate

A solution of 2.50 g (4.38 mmol)(R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylatein 50 mL DCM was combined with 250 mg 10% Pd/C and hydrogenated at RTand 3 bar hydrogen pressure for 4.5 h. To complete the reaction afurther 250 mg of catalyst were added, the mixture was hydrogenated for12 h at 40° C., combined with 25 mL THF and 250 mg catalyst andhydrogenated for a further 12 h at 40° C. The catalyst was removed bysuction filtering and the filtrate was concentrated by evaporation i.vac. The residue was stirred with DIPE, suction filtered and dried.

Yield: 1.87 g (89% of theory)

ESI-MS: (M−H)⁻=479

Retention time (HPLC-MS): 3.5 min (method B)

2d)(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate

A solution of 100 mg (0.21 mmol)(R)-1-carboxy-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate,74 mg (0.23 mmol) TBTU and 35 μL (0.26 mmol) triethylamine in 1 mL DMFwas stirred for 1 h at RT. Then 39 mg (0.21 mmol)1-methyl-4-piperidin-4-yl-piperazine was added and the reaction mixturewas stirred for another 5 h at RT. The reaction solution was purified byHPLC without any further working up. The fractions containing theproduct were combined and lyophilised.

Yield: 40 mg (30% of theory)

ESI-MS: (M+H)⁺=646

Retention time (HPLC-MS): 2.7 min (method B)

The following compounds were prepared analogously from in each case 100mg (Examples 2.1 to 2.7) or 150 mg (Example 2.8)(R)-1-carboxy-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

Example —R³—R⁴ Yield (%) Mass spectrum Retention time HPLC (method) 2.1

22 646 [M + H]⁺ 2.5 min (B) 2.2

28 645 [M + H]⁺ 3.0 min (B) 2.3

29 631 [M + H]⁺ 3.0 min (B) 2.4

25 591 [M + H]⁺ 2.8 min (B) 2.5

28 633 [M + H]⁺ 2.9 min (B) 2.6

24 631 [M + H]⁺ 3.1 min (B) 2.7

23 721 [M + H]⁺ 3.4 min (B)

The following compounds were prepared analogously from in each case 250mg (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate(Example 2b) and the corresponding amount of amine:

Example —R³—R⁴ Yield (%) Mass spectrum Retention time HPLC (method) 2.8

17 807 [M + H]⁺ 3.2 min (B) 2.9

13 808 [M + H]⁺ 3.1 min (B)

EXAMPLE 2.10(R)-2-(4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate

A solution of 51 mg (0.07 mmol)(R)-2-(1′-benzyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate(Example 2.7) in 10 mL MeOH was combined with 5 mg 10% Pd/C andhydrogenated at RT and 3 bar hydrogen pressure until the reaction cameto an end. The catalyst was removed by suction filtering and the residuewas purified by HPLC. The fractions containing the product were combinedand lyophilised.

Yield: 15 mg (45% of theory)

ESI-MS: (M−H)⁻=629

Retention time (HPLC-MS): 2.5 min (method B)

EXAMPLE 2.11(R)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate

A solution of 58 mg (0.07 mmol)(R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-(1′-ethoxy-carbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate(Example 2.8) in 5 mL EtOH was combined with 10 mg 10% Pd/C andhydrogenated at RT and 3 bar hydrogen pressure until the reaction cameto an end. The catalyst was removed by suction filtering and the residuewas purified by HPLC. The fractions containing the product were combinedand lyophilised.

Yield: 23 mg (45% of theory)

ESI-MS: (M+H)⁺=717

Retention time (HPLC-MS): 3.1 min (method B)

EXAMPLE 2.12(R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate

A solution of 1.2 mg (0.05 mmol) LiOH in 2 mL water was added to asolution of 21 mg (0.03 mmol)(R)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylatein 3 mL THF and the reaction mixture was stirred for 1 h at RT. The THFwas evaporated down i.vac., the residue was acidified with 1 M HCl andagain evaporated down i.vac. The residue was purified by HPLC, thefractions containing the product were combined and lyophilised.

Yield: 12 mg (58% of theory)

ESI-MS: (M+H)⁺=689

Retention time (HPLC-MS): 2.9 min (method B)

EXAMPLE 2.13(R)-2-[4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate

Prepared analogously to Example 2.11 from 47 mg (0.06 mmol)(R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-[4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate(Example 2.9).

Yield: 18 mg (43% of theory)

ESI-MS: (M+H)⁺=718

Retention time (HPLC-MS): 3.0 min (method B)

EXAMPLE 2.14(R)-2-[4-(4-carboxymethyl-piperazin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate

Prepared analogously to Example 2.12 from 38 mg (0.05 mmol)(R)-2-[4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylateand 2.1 mg (0.09 mmol) LiOH.

Yield: 20 mg (55% of theory)

ESI-MS: (M+H)⁺=690

Retention time (HPLC-MS): 2.7 min (method B)

EXAMPLE 3 (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-{1′-[2-(2-oxo-pyrrolidin-1-yl)-ethoxycarbonyl-methyl]-4,4′-bipiperidinyl-1-yl}-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

3a)(R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

0.99 g (3.90 mmol) ethyl [4,4′]bipiperidinyl-1-yl-acetate were added atRT to a solution of 2.00 g (3.50 mmol)(R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 1g), 1.25 g (3.90 mmol) TBTU and 0.67 mL (3.90 mmol)ethyldiisopropylamine in 20 mL THF and 5 mL DMF and the reaction mixturewas stirred overnight. 15% K₂CO₃ solution was added, the mixture wasextracted exhaustively with EtOAc, the combined organic phases werewashed with saturated NaCl solution and dried on Na₂SO₄. After theelimination of the desiccant and solvent the product was obtained, whichwas reacted further without purification.

Yield: 2.80 g (99% of theory)

ESI-MS: (M+H)⁺=809

Retention time (HPLC-MS): 4.1 min (method B)

3b)(R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

2.80 g (3.47 mmol)(R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 30 mL MeOH were combined with 300 mg 10% Pd/C and hydrogenated at RTand 3 bar hydrogen until the reaction came to an end (24 h). Thecatalyst was removed by suction filtering and the solvent wasconcentrated by evaporation i. vac. The residue was dissolved in 30 mLTHF, combined with a solution of 127 mg (5.33 mmol) LiOH in 10 mL waterand the reaction mixture was stirred overnight at RT. The mixture wasevaporated down i.vac. and the residue was purified by chromatography(silica gel, gradient DCM to DCM/MeOH/NH₃ 70:30:3). The fractionscontaining the product were combined, concentrated by evaporation i.vac., the residue was triturated with DIPE, suction filtered and dried.

Yield: 1.80 g (75% of theory)

ESI-MS: (M+H)⁺=690

R_(f)=0.16 (silica gel, DCM/MeOH/Cyc/NH₃ 70:15:15:2)

3c) (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-{1′-[2-(2-oxo-pyrrolidin-1-yl)-ethoxycarbonyl-methyl]-4,4′-bipiperidinyl-1-yl}-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 80 mg (0.12 mmol)(R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,45 mg (0.14 mmol) TBTU and 32 μL (0.23 mmol) triethylamine in 1.2 mL DMFwas stirred for 1 h at RT. Then 26 mg (0.23 mmol)1-(2-hydroxy-ethyl)-pyrrolidin-2-one were added and the reaction mixturewas stirred overnight at RT. The reaction solution was mixed with 5drops of formic acid, filtered through a syringe filter and purifieddirectly by HPLC without any further working up. The fractionscontaining the product were combined, extracted with 30 mL EtOAc, theorganic phase was made alkaline with 5% NaHCO₃ solution, separated offand dried on Na₂SO₄. After the elimination of the desiccant and solventthe residue was triturated with DIPE, suction filtered and dried.

Yield: 26 mg (28% of theory)

ESI-MS: (M+H)⁺=801

Retention time (HPLC-MS): 3.1 min (method B)

EXAMPLE 3.1 (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[1′-(2-methoxy-ethoxycarbonylmethyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 3c from 80 mg (0.12 mmol)(R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 18 μL (0.23 mmol) 2-methoxy-ethanol.

Yield: 33 mg (38% of theory)

ESI-MS: (M+H)⁺=748

Retention time (HPLC-MS): 3.2 min (method B)

EXAMPLE 3.2(R)-2-(1′-hexyloxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 80 mg (0.12 mmol)(R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,45 mg (0.14 mmol) TBTU and 32 μL (0.23 mmol) triethylamine in 1.2 mL DMFwas stirred for 1 h at RT. Then 29 μL (0.23 mmol) 1-hexanol were addedand the reaction mixture was stirred for 4 days at RT. The mixture wasevaporated down i.vac., the residue was taken up in 30 mL EtOAc, theorganic phase was washed with 20 mL 5% NaHCO₃ solution and dried onNa₂SO₄. After the elimination of the desiccant and solvent the residuewas purified by chromatography (silica gel, gradient DCM/isopropanol95:5 to DCM/isopropanol 90:10). The fractions containing the productwere concentrated by evaporation i. vac., the residue was trituratedwith DIPE, suction filtered and dried.

Yield: 24 mg (27% of theory)

ESI-MS: (M+H)⁺=774

Retention time (HPLC-MS): 4.0 min (method B)

EXAMPLE 3.3(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-{1′-[2-(2-oxo-piperidin-1-yl)-ethoxycarbonyl-methyl]-4,4′-bipiperidinyl-1-yl}-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 3c from 80 mg (0.12 mmol)(R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 33 mg (0.23 mmol) 1-(2-hydroxyethyl)-piperidin-2-one. After theelimination of the desiccant and solvent the residue was taken up in DCMand again purified by chromatography (silica gel, DCM/EtOH/NH₃95:5:0.5). The fractions containing the product were combined,concentrated by evaporation i. vac., triturated with DIPE, suctionfiltered and dried.

Yield: 23 mg (24% of theory)

ESI-MS: (M+H)⁺=815

Retention time (HPLC-MS): 3.2 min (method B)

EXAMPLE 3.4(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-[1′-(2-morpholin-4-yl-ethoxycarbonylmethyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 3c from 80 mg (0.12 mmol)(R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 17 μL (0.14 mmol) 2-morpholin-4-yl-ethanol. After purification byHPLC the product obtained was dissolved in 10 mL DCM and stirred with 5mL of 5% NaHCO₃ solution. The organic phase was separated off and driedon Na₂SO₄. After the elimination of the desiccant and solvent theresidue was triturated with diethyl ether, suction filtered and dried.

Yield: 32 mg (34% of theory)

ESI-MS: (M+H)⁺=803

Retention time (HPLC-MS): 2.7 min (method B)

EXAMPLE 3.5(R)-2-(1′-dimethylcarbamoylmethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 3c from 100 mg (0.15 mmol)(R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 16 mg (0.16 mmol) 2-hydroxy-N,N-dimethyl-acetamide. Afterpurification by HPLC the fractions containing the product were combinedand lyophilised.

Yield: 45 mg (40% of theory)

ESI-MS: (M+H)⁺=775

Retention time (HPLC-MS): 3.1 min (method B)

EXAMPLE 4(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-{1-[2-(2-oxo-pyrrolidin-1-yl)-ethoxycarbonyl-methyl]-piperidin-4-yl}-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

4a)(R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 2.80 g (4.90 mmol)(R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 1g), 1.80 g (5.61 mmol) TBTU and 3.10 mL (22.08 mmol)triethylamine in 30 mL DMF was stirred for 1 h at RT. Then 2.00 g (5.48mmol) ethyl (4-piperazin-1-yl-piperidin-1-yl)-acetate were added. Thereaction mixture was stirred for 1 h at RT, poured onto 150 mL 15% K₂CO₃solution and extracted with 200 mL EtOAc. The organic phase wasextracted with 150 mL of 10% citric acid solution, the aqueous phase wasmade alkaline with 15% K₂CO₃ solution and extracted with 200 mL EtOAc.The organic phase was concentrated by evaporation i. vac. and theresidue was purified by chromatography (silica gel, EtOH).

Yield: 2.00 g (51% of theory)

ESI-MS: (M+H)⁺=809

Retention time (HPLC-MS): 3.9 min (method B)

4b)(R)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

2.00 g (2.47 mmol) of(R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 25 mL EtOH were combined with 200 mg 10% Pd/C and hydrogenated at RTand 3 bar hydrogen until the reaction came to an end. The catalyst wasremoved by suction filtering and the solvent was concentrated byevaporation i. vac. The residue was reacted further without anypurification by chromatography.

Yield: 1.77 g (100% of theory)

ESI-MS: (M+H)⁺=719

Retention time (HPLC-MS): 2.6 min (method B)

4c)(R)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 96 mg (4.00 mmol) LiOH in 5 mL water was added at RT to asolution of 1.77 g (2.46 mmol) of(R)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 20 mL THF and the reaction solution was stirred overnight at RT. Themixture was evaporated down i.vac., the residue was taken up in 10 mLwater and the aqueous phase was washed with 10 mL EtOAc. The aqueousphase was combined with 4 mL of 1 M HCl and this was again washed with10 mL EtOAc. The aqueous phase was concentrated by evaporation i. vac.and dried. The product which contained LiCl was further reacted withoutpurification.

Yield: 1.70 g (100% of theory)

ESI-MS: (M+H)⁺=691

Retention time (HPLC-MS): 2.7 min (method B)

4d)(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-{1-[2-(2-oxo-pyrrolidin-1-yl)-ethoxycarbonyl-methyl]-piperidin-4-yl}-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

58 mg (0.18 mmol) TBTU were added at RT to a solution of 100 mg (0.15mmol)(R)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,18 μL (0.16 mmol) 1-(2-hydroxy-ethyl)-pyrrolidin-2-one and 50 μL (0.36mmol) triethylamine in 1.5 mL DMF and the reaction mixture was stirredfor 2 h at RT. 10 mL of semisaturated NaHCO₃ solution were added, theprecipitate formed was filtered off, dissolved in 1.5 mL DMF andpurified by HPLC. The fractions containing the product were combined andlyophilised.

Yield: 13 mg (11% of theory)

ESI-MS: (M+H)⁺=802

Retention time (HPLC-MS): 2.9 min (method B)

The following compounds were prepared analogously from in each case 100mg(R)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of the alcohol component:

Example R Yield (%) Mass spectrum Retention time HPLC (method) 4.1

17 733 [M + H]⁺ 3.0 min (B) 4.2

38 747 [M + H]⁺ 3.3 min (B) 4.3

11 776 [M + H]⁺ 2.9 min (B)

EXAMPLE 4.4(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-{1-[2-(2-methoxy-ethoxy)-ethoxycarbonylmethyl]-piperidin-4-yl}-piperazin-1-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 4d from 70 mg (0.10 mmol) of(R)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 13 μL (0.11 mmol) 2-(2-methoxy-ethoxy)-ethanol. The reactionsolution was purified by HPLC without any further working up; thefractions containing the product were combined and lyophilised.

Yield: 54 mg (68% of theory)

ESI-MS: (M+H)⁺=793

Retention time (HPLC-MS): 2.8 min (method B)

EXAMPLE 4.5(R)-2-[4-(1-hexyloxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 4d from 934 mg (1.35 mmol)(R)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 190 μL (0.11 mmol) 1-hexanol. The reaction solution was combinedwith 30 mL semisaturated NaHCO₃ solution, extracted with 50 mL EtOAc andthe organic phase was dried on Na₂SO₄. After the elimination of thedesiccant and solvent the residue was purified by chromatography (silicagel, EtOAc/MeOH/NH₃ 90:10:1).

Yield: 199 mg (19% of theory)

ESI-MS: (M+H)⁺=775

Retention time (HPLC-MS): 3.6 min (method B)

EXAMPLE 5(R)-2-[1′-(2-dimethylcarbamoylmethoxycarbonyl-ethyl)-4,4′-bipiperidinyl-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

5a)(R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-[1′-(2-ethoxycarbonyl-ethyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 3a from 2.00 g (3.50 mmol)(R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl (Example 1g) and1.05 g (3.90 mmol) 3-[4,4′]bipiperidinyl-1-yl-propionate ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate.

Yield: 2.90 g (100% of theory)

ESI-MS: (M+H)⁺=823

Retention time (HPLC-MS): 4.0 min (method B)

5b)(R)-2-[1′-(2-carboxy-ethyl)-4,4′-bipiperidinyl-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,45-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 3b from 2.90 g (3.35 mmol)(R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-[1′-(2-ethoxycarbonyl-ethyl)-4,4′-bipiperidinyl-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,300 mg 10% Pd/C (hydrogenation) and 128 mg LiOH (ester hydrolysis).

Yield: 1.70 g (71% of theory)

ESI-MS: (M+H)⁺=704

R_(f)=0.20 (silica gel, DCM/MeOH/Cyc/NH₃ 70:15:15:2)

5c)(R)-2-[1′-(2-dimethylcarbamoylmethoxycarbonyl-ethyl)-4,4′-bipiperidinyl-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 1i from 100 mg (0.14 mmol)(R)-2-[1′-(2-carboxy-ethyl)-4,4′-bipiperidinyl-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 16 mg (0.16 mmol) 2-hydroxy-N,N-dimethyl-acetamide.

Yield: 35 mg (31% of theory)

ESI-MS: (M+H)⁺=789

Retention time (HPLC-MS): 3.6 min (method B)

EXAMPLE 6

Ethyl1′-{(R)-3-(4-hydroxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylate

6a) ethyl1′-{(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylate

A solution of 400 mg (0.70 mmol)(R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 1g), 250 mg (0.78 mmol) TBTU and 0.12 mL (3.73 mmol)triethylamine in 20 mL THF were stirred for 1 h at RT. Then 0.4 mL (2.87mmol) triethylamine and 270 mg (0.86 mmol) ethyl[1,4′]bipiperidinyl-4-carboxylate (used as the bis-hydrochloride salt)were added. The reaction mixture was stirred for 24 h at RT, dilutedwith EtOAc, washed with saturated NaHCO₃ solution and the organic phasewas dried on Na₂SO₄. After the elimination of the desiccant and solventthe residue was purified by chromatography (Alox activity stage II-III,gradient DCM/EtOH 40:1 to DCM/EtOH 30:1).

Yield: 440 mg (79% of theory)

ESI-MS: (M+H)⁺=794

Retention time (HPLC-MS): 4.1 min (method B)

6b) ethyl1′-{(R)-3-(4-hydroxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]propionyl}-1,4′-bipiperidinyl-4-carboxylate

80 mg (0.10 mmol) ethyl1′-{(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylatein 10 mL EtOH were combined with 30 mg 10% Pd/C and hydrogenated at 50°C. and 50 psi hydrogen for 1 h. The catalyst was removed by suctionfiltering and the solvent was concentrated by evaporation i. vac. Theresidue was triturated with diethyl ether, suction filtered and dried.

Yield: 37 mg (52% of theory)

ESI-MS: (M+H)⁺=704

Retention time (HPLC-MS): 3.2 min (method B)

EXAMPLE 6.1

1′-{(R)-3-(4-hydroxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylicacid

6.1a)1′-{(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]propionyl}-1,4′-bipiperidinyl-4-carboxylicacid

A solution of 20 mg (0.84 mmol) LiOH in 3 mL water was added to asolution of 350 mg (0.44 mmol) ethyl1′-{(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylate(Example 6a) in 15 mL THF and the reaction mixture was stirred for 3 hat RT. It was diluted with a little water, the THF was eliminated i.vac.and 4 M HCl was added to the aqueous solution while cooling with iceuntil an acidic reaction was obtained. The mixture was extractedexhaustively with DCM and dried on Na₂SO₄. After the elimination of thedesiccant and solvent the residue was triturated with diethyl ether,suction filtered and dried, while the product was obtained as thehydrochloride salt.

Yield: 310 mg (88% of theory)

ESI-MS: (M+H)⁺=766

6.1 b)1′-{(R)-3-(4-hydroxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]propionyl}-1,4′-bipiperidinyl-4-carboxylicacid

100 mg (0.13 mmol)1′-{(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylicacid in 10 mL MeOH were combined with 30 mg 10% Pd/C and hydrogenated at50° C. and 3 bar hydrogen for 2 h. The catalyst was removed by suctionfiltering and the solvent was concentrated by evaporation i. vac. Theresidue was triturated with diethyl ether, suction filtered and dried.

Yield: 64 mg (72% of theory)

ESI-MS: (M+H)⁺=676

Retention time (HPLC-MS): 3.0 min (method B)

EXAMPLE 6.2 Dimethylcarbamoyl methyl 1′-{(R)-3-(4-hydroxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylate

6.2a) dimethylcarbamoylmethyl1′-{(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]propionyl}-1,4′-bipiperidinyl-4-carboxylate

30 mg (0.29 mmol) 2-hydroxy-N,N-dimethyl-acetamide were added at RT to asolution of 200 mg (0.25 mmol)1′-{(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylicacid (Example 6.1a), 90 mg (0.28 mmol) TBTU and 80 μL (3.73 mmol)triethylamine in 1.8 mL DMF and this was stirred for 20 h at RT. Thereaction mixture was poured onto saturated NaHCO₃ solution, theprecipitate formed was suction filtered and dried. Further purificationwas carried out by HPLC, the fractions containing the product werecombined and lyophilised.

Yield: 100 mg (47% of theory)

ESI-MS: (M+H)⁺=851

Retention time (HPLC-MS): 3.9 min (method B)

6.2b) dimethylcarbamoylmethyl1′-{(R)-3-(4-hydroxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylate

95 mg (0.11 mmol) dimethylcarbamoylmethyl1′-{(R)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylatein 10 mL THF were combined with 50 mg 10% Pd/C and hydrogenated at 50°C. and 50 psi hydrogen for 6 h. The catalyst was removed by suctionfiltering and the solvent was concentrated by evaporation i. vac. Theresidue was triturated with diethyl ether, suction filtered and dried.

Yield: 52 mg (61% of theory)

ESI-MS: (M+H)⁺=761

Retention time (HPLC-MS): 3.1 min (method B)

EXAMPLE 7(R)-2-(4-ethoxycarbonylmethoxy-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

7a)(R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-(4-ethoxycarbonylmethoxy-1,4′-bipiperidinyl-1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

220 mg (0.64 mmol) ethyl ([1,4′]bipiperidinyl-4-yloxy)-acetate (used asthe bis-hydrochloride salt) were added at RT to a solution of 330 mg(0.58 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 1g), 200 mg (0.62 mmol) TBTU and 0.30 mL (2.16 mmol)triethylamine in 3 mL DMF and the mixture was stirred for 4 h. Thereaction mixture was combined with saturated NaHCO₃ solution whilecooling with ice and the precipitate was suction filtered. This wasdissolved in a little DCM and EtOH and purified by HPLC; the fractionscontaining the product were combined and lyophilised.

Yield: 340 mg (72% of theory)

ESI-MS: (M+H)⁺=824

Retention time (HPLC-MS): 4.2 min (method B)

7b)(R)-2-(4-ethoxycarbonylmethoxy-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

340 mg (0.41 mmol)(R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-(4-ethoxycarbonylmethoxy-1,4′-bipiperidinyl -1′-yl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 20 mL EtOH were combined with 100 mg 10% Pd/C and hydrogenated at 50°C. and 50 psi hydrogen for 2 h. The catalyst was removed by suctionfiltering and the solvent was concentrated by evaporation i. vac.

Yield: 270 mg (89% of theory)

ESI-MS: (M+H)⁺=734

Retention time (HPLC-MS): 3.3 min (method B)

EXAMPLE 7.1(R)-2-(4-carboxymethoxy-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 15 mg (0.63 mmol) LiOH in 5 mL water was added to asolution of 180 mg (0.25 mmol)(R)-2-(4-ethoxycarbonylmethoxy-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 15 mL THF and the reaction mixture was stirred for 4 h at RT. 0.66 mLof 1 M HCl were added and the mixture was concentrated by evaporation i.vac. The residue was taken up in a little DCM/MeOH (7:3) and filteredthrough silica gel. The filtrate was concentrated by evaporation i.vac., the residue was triturated with diethyl ether, suction filteredand dried.

Yield: 173 mg (100% of theory)

ESI-MS: (M+H)⁺=706

Retention time (HPLC-MS): 2.9 min (method B)

EXAMPLE 8(R)-2-[4-(2-ethoxycarbonyl-ethyl)-1,4′-bipiperidinyl-1′-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

410 mg (1.20 mmol) ethyl 3-[1,4′]bipiperidinyl-4-yl-propionate (used asthe bis-hydrochloride salt) were added at RT to a solution of 500 mg(1.04 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 1h), 385 mg (1.20 mmol) TBTU and 0.48 mL (3.40 mmol)triethylamine in 10 mL DMF and the mixture was stirred for 2 h. Thereaction mixture was purified by HPLC without any further working up.The fractions containing the product were combined, concentrated byevaporation i. vac. and the residue was stirred with saturated NaHCO₃solution.

The precipitate formed was filtered off and dried.

Yield: 310 mg (41% of theory)

ESI-MS: (M+H)⁺=732

Retention time (HPLC-MS): 2.4 min (method B)

EXAMPLE 8.1(R)-2-[4-(2-carboxy-ethyl)-1,4′-bipiperidinyl-1′-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 2.6 mg (0.11 mmol) LiOH in 1 mL water was added to asolution of 50 mg (0.07 mmol)(R)-2-[4-(2-ethoxycarbonyl-ethyl)-1,4′-bipiperidinyl-1′-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 3 mL THF and the reaction mixture was stirred for 4 h at RT. The THFwas eliminated in a nitrogen current and the crude product was purifiedby HPLC. The fractions containing the product were combined andlyophilised.

Yield: 32 mg (67% of theory)

ESI-MS: (M+H)⁺=704

Retention time (HPLC-MS): 3.1 min (method B)

EXAMPLE 9(R)-2-{4-[1-(3-ethoxycarbonyl-propyl)-piperidin-4-yl]-piperazin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 8 from 500 mg (1.04 mmol)(R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 1h) and 385 mg (1.20 mmol) ethyl4-(4-piperazin-1-yl-piperidin-1-yl)-butanoate.

Yield: 85 mg (11% of theory)

ESI-MS: (M+H)⁺=747

Retention time (HPLC-MS): 2.8 min (method B)

EXAMPLE 9.1(R)-2-{4-[1-(3-carboxy-propyl)-piperidin-4-yl]-piperazin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Prepared analogously to Example 8.1 from 50 mg (0.07 mmol)(R)-2-{4-[1-(3-ethoxycarbonyl-propyl)-piperidin-4-yl]-piperazin-1-yl}-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand 2.6 mg (0.11 mmol) LiOH.

Yield: 24 mg (50% of theory)

ESI-MS: (M+H)⁺=719

Retention time (HPLC-MS): 2.7 min (method B)

EXAMPLE 10 (R)-1-(4-hydroxy-3-methoxy-5-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

10a) 4-bromo-2-methoxy-6-methyl-phenol

A solution of 56.2 g (0.32 mol) N-bromosuccinimide in 1700 mL AcOH wasadded dropwise within 5.5 h to a solution of 42.3 g (0.31 mol)2-methoxy-6-methyl-phenol in 450 mL AcOH and the mixture was stirred for16 h at RT. The reaction mixture was concentrated by evaporation i. vac.and the residue was taken up in DCM. The organic phase was washed with5% NaHCO₃ and saturated NaCl solution, dried on Na₂SO₄ and concentratedby evaporation i. vac. The red oil was used in the next reaction stepwithout any further purification.

Yield: 65.9 g (66% of theory)

R_(f)=0.32 (silica gel, hexane/EtOAc 4:1)

Retention time (HPLC-MS): 11.1 min (method D)

10b) 2-benzyloxy-5-bromo-1-methoxy-3-methyl-benzene

45.7 g (0.33 mol) K₂CO₃ and a solution of 40.3 mL (0.33 mol)benzylbromide were added at RT to a solution of 65.9 g (0.26 mol)4-bromo-2-methoxy-6-methyl-phenol in 330 mL DMF and the mixture wasstirred for 18 h at RT. The mixture was filtered, concentrated byevaporation i. vac. and the residue was taken up in diethyl ether. Theorganic phase was washed with water, 5% Na₂CO₃ and NaCl solution, driedon Na₂SO₄ and concentrated by evaporation i. vac. The crude product wasused in the next reaction step without any further purification.

Yield: 92.2 g (81% of theory)

R_(f)=0.56 (silica gel, hexane/EtOAc 4:1)

Retention time (HPLC-MS): 16.3 min (method D)

10c) 4-benzyloxy-3-methoxy-5-methyl-benzaldehyde

96 mL (240 mmol) n-butyllithium (2.5 M in hexane) were added dropwise at−75° C. to a solution of 61.2 g (119.5 mmol)2-benzyloxy-5-bromo-1-methoxy-3-methyl-benzene in 240 mL THF and themixture was stirred for 15 min at −75° C. A solution of 31 mL (402 mmol)DMF in 30 mL THF was added dropwise, the mixture was heated to 0° C. andstirred for another 2 h. The reaction was combined with saturated NH₄Clsolution, diluted with 150 mL water and the phases were separated. Theaqueous phase was extracted exhaustively with diethyl ether. Thecombined organic phases were washed with saturated NaCl solution, driedon Na₂SO₄ and concentrated by evaporation i. vac. Column chromatography(silica gel, hexane/EtOAc 85:15) yielded the product in the form of ayellow oil.

Yield: 27.1 g (88% of theory)

R_(f)=0.32 (silica gel, hexane/EtOAc 4:1)

Retention time (HPLC-MS): 13.3 min (method D)

10d) 2-acetylamino-3-(4-benzyloxy-3-methoxy-5-methyl-phenyl)-acrylicacid

A suspension of 27.0 g (105.4 mmol)4-benzyloxy-3-methoxy-5-methyl-benzaldehyde, 18.5 g (158.0 mmol)N-acetylglycine and 12.96 g (158.0 mmol) NaOAc in 120 mL aceticanhydride was heated to 11 5° C. under nitrogen for 3.5 h. At 100° C. 60mL water were slowly added dropwise and the mixture was stirred for 1 h.The reaction mixture was cooled to RT, poured into water and the aqueousphase was exhaustively extracted with EtOAc. The combined organic phaseswere washed with saturated NaCl solution, dried on Na₂SO₄ andconcentrated by evaporation i. vac. The residue was triturated withisopropanol, the solid obtained was washed with isopropanol, diethylether and a little acetone and dried i.vac. at 45° C.

Yield: 21.2 (57% of theory)

R_(f)=0.24 (silica gel, hexane/EtOAc 4:1)

Retention time (HPLC-MS): 9.4 min (method D)

10e) 3-(4-benzyloxy-3-methoxy-5-methyl-phenyl)-2-oxo-propionic acid

The product was obtained analogously to Example 1 c starting from 20.0 g(56.3 mmol)2-acetylamino-3-(4-benzyloxy-3-methoxy-5-methyl-phenyl)-acrylic acid.The crude product was used in the next reaction step without any furtherpurification.

Yield: 15.6 g (53% of theory)

Retention time (HPLC-MS): 11.9 min (method D)

10f) (R)-3-(4-benzyloxy-3-methoxy-5-methyl-phenyl)-2-hydroxy-propionicacid

The product was prepared analogously to Example 1d starting from 16.0 g(50.90 mmol) 3-(4-benzyloxy-3-methoxy-5-methyl-phenyl)-2-oxo-propionicacid.

Yield: 7.63 g (47% of theory)

Retention time (HPLC-MS): 9.8 min (method D)

10g) methyl(R)-3-(4-benzyloxy-3-methoxy-5-methyl-Phenyl)-2-hydroxy-propionate

The product was prepared analogously to Example 1e starting from 7.6 g(24.02 m mol)(R)-3-(4-benzyloxy-3-methoxy-5-methyl-phenyl)-2-hydroxy-propionic acid.

Yield: 6.84 g (86% of theory)

Retention time (HPLC-MS): 11.7 min (method D)

10h)(R)-2-(4-benzyloxy-3-methoxy-5-methyl-Phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

The product was prepared analogously to Example 1f starting from 6.8 g(20.6 m mol) methyl(R)-3-(4-benzyloxy-3-methoxy-5-methyl-phenyl)-2-hydroxy-propionate inacetonitrile.

Yield: 8.16 g (66% of theory)

ESI-MS: (M+H)⁺=602

Retention time (HPLC-MS): 14.1 min (method D)

10i) (R)-2-(4-benzyloxy-3-methoxy-5-methyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

The product was prepared analogously to Example 1g starting from 8.16 g(13.65 m mol)(R)-2-(4-benzyloxy-3-methoxy-5-methyl-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate.

Yield: 7.83 g (98% of theory)

ESI-MS: (M+H)⁺=588

Retention time (HPLC-MS): 12.2 min (method D)

10j) (R)-1-carboxy-2-(4-hydroxy-3-methoxy-5-methyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

The product was prepared analogously to Example 1h starting from 7.80 g(13.27 mmol)(R)-2-(4-benzyloxy-3-methoxy-5-methyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate.

Yield: 5.33 g (80% of theory)

ESI-MS: (M+H)⁺=498

Retention time (HPLC-MS): 8.4 min (method D)

10k) (R)-1-(4-hydroxy-3-methoxy-5-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

84 mg (0.22 mmol) HATU was added at RT under nitrogen to a solution of100 mg (0.20 mmol)(R)-1-carboxy-2-(4-hydroxy-3-methoxy-5-methyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,37.8 μL (0.22 mmol) ethyldiisopropylamine and 44 mg (0.24 mmol)1-methyl-4-(piperidin-4-yl)-piperazine in 5 mL DMF and the mixture wasstirred for 3 h. The reaction mixture was concentrated by evaporation i.vac. at 50° C. and the crude product was purified by preparativeHPLC-MS.

Yield: 89 mg (57% of theory)

ESI-MS: (M+H)⁺=663

Retention time (HPLC-MS): 5.6 min (method D)

The following compounds were prepared analogously from in each case 100mg (Examples 10.1 and 10.2) or 150 mg (Examples 10.3 to 10.5) of(R)-1-carboxy-2-(4-hydroxy-3-methoxy-5-methyl -phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

Example —R³—R⁴ Yield (%) Mass spectrum Retention time HPLC (method) 10.1

60 663 [M + H]⁺ 3.1 min (D) 10.2

71 662 [M + H]⁺ 3.6 min (D) 10.3

quant. 739 [M + H]⁺ 3.8 min (D) 10.4

quant. 749 [M + H]⁺ 4.0 min (D) 10.5

quant. 748 [M + H]⁺ 6.3 min (D)

EXAMPLE 10.6(R)-1-(4-hydroxy-3-methoxy-5-methyl-benzyl)-2-oxo-2-(4-piperidin-4-yl-piperazin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 220 mg (0.29 mmol)(R)-2-[4-(1-tert-butoxycarbonyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3-methoxy-5-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 10.4) in 3 mL formic acid was stirred for 4 h at RT and thenconcentrated by evaporation i. vac. at 40° C. The crude product waspurified by preparative HPLC-MS.

Yield: 13 mg (6% of theory)

ESI-MS: (M+H)⁺=649

Retention time (HPLC-MS): 3.8 min (method D)

EXAMPLE 10.7(R)-2-4,4′-bipiperidinyl-1-yl-1-(4-hydroxy-3-methoxy-5-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

The product was prepared analogously to Example 10.6 starting from 210mg (0.28 mmol) tert. butyl1′-{(R)-3-(4-hydroxy-3-methoxy-5-methyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-4,4′-bipiperidinyl-1-carboxylate(Example 10.5).

Yield: 164 mg (77% of theory)

ESI-MS: (M+H)⁺=648

Retention time (HPLC-MS): 3.6 min (method D)

EXAMPLE 10.8(R)-1-(4-hydroxy-3-methoxy-5-methyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A suspension of 222 mg (0.30 mmol)(R)-2-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3-methoxy-5-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 10.3) and 60 mg 10% Pd/C in 10 mL EtOH and 6 mL MeOH washydrogenated at 60 psi and RT for 72 h. The catalyst was filtered offand the crude product was purified by HPLC-MS.

Yield: 64 mg (28% of theory)

ESI-MS: (M+H)⁺=649

Retention time (HPLC-MS): 3.2 min (method D)

EXAMPLE 11(R)-1-(3-ethyl-4-hydroxy-5-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

11a) 2-ethyl-6-methyl-phenol

19.4 mL (0.23 mmol) concentrated HCl and a solution of 16.1 g (0.23mmol) sodium nitrite in water (approx. 70 mL) were added at 0° C. to asolution of 30 g (222 mmol) 2-ethyl-6-methyl-aniline in 135 mL EtOH andstirred for 15 min. This mixture was added at 45° C. to a solution of10.5 mL of concentrated H₂SO₄ in 300 mL water and at the end of theaddition heated to 70° C. The aqueous phase was cooled to RT andexhaustively extracted with EtOAc. The combined organic phases wereextracted with 1 M NaOH solution. The aqueous phase was washed with DCM,acidified to pH 1 with 4 N HCl solution and extracted with DCM. Theorganic phase was washed with saturated NaCl solution, dried on Na₂SO₄and concentrated by evaporation i. vac. The crude product was used inthe subsequent reaction step without any further purification.

Yield: 12.0 g (40% of theory)

11b) 4-bromo-2-ethyl-6-methyl-phenol

A solution of 12.7 mL (247 mmol) bromine in 10 mL chloroform was addeddropwise at RT to a solution of 33.6 g (247 mmol)2-ethyl-6-methyl-phenol in 350 mL chloroform and the mixture was stirredfor 2 h. The reaction mixture was combined with an aqueous NaHSO₃solution and stirred for 20 min. The phases were separated and theorganic phase was washed with saturated NaCl solution, dried on Na₂SO₄and concentrated by evaporation i. vac. Column chromatography (silicagel, Cyc/EtOAc 9:1) yielded the product.

Yield: 39.8 g (75% of theory)

ESI-MS: (M+H)⁺=214/216 (Br)

Retention time (HPLC-MS): 6.3 min (method D)

11c) 2-benzyloxy-5-bromo-1-ethyl-3-methyl-benzene

A suspension of 39.8 g (185 mmol) 4-bromo-2-ethyl-6-methyl-phenol, 63.9g (0.46 mmol) K₂CO₃ and 22.0 mL (185 mmol) benzyl bromide in 450 mLacetonitrile was refluxed for 3 h, cooled to RT and concentrated byevaporation i. vac. The residue was combined with EtOAc, the organicphase was washed with water and saturated NaCl solution, dried on Na₂SO₄and concentrated by evaporation i. vac.

Yield: 54.5 g (96% of theory)

ESI-MS: (M+H)⁺=304/306 (Br)

Retention time (HPLC-MS): 9.4 min (method D)

11d) methyl(Z,E)-2-acetylamino-3-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-acrylate

Prepared analogously to Example 1b from 50.4 g (165.1 mmol)2-benzyloxy-5-bromo-1-ethyl-3-methyl-benzene and 28.9 g (198.2 mmol)methyl 2-acetylamino-acrylate.

Yield: 41.0 g (68% of theory)

ESI-MS: (M+H)⁺=368

Retention time (HPLC-MS): 4.5 min (method B)

11e) 3-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-2-oxo-propionic acid

200 mL of 4 M HCl were added to a solution of 41.0 g (112 mmol) methyl(Z,E)-2-acetylamino-3-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-acrylate in300 mL 1,4-dioxane and the reaction solution was heated to 130° C. (bathtemperature) for 7 h. The organic phase was separated off while hot,concentrated by evaporation i. vac. and the residue obtained wasrecrystallised from toluene.

Yield: 9.6 g (28% of theory)

ESI-MS: (M+H)⁺=312

Retention time (HPLC-MS): 4.1 min (method B)

11f) (R)-3-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-2-hydroxy-propionicacid

Under an argon atmosphere a solution of 9.59 g (30.7 mmol)3-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-2-oxo-propionic acid in 25 mLTHF was combined with 4.26 mL (31.0 mmol) triethylamine, stirred for 5min and cooled to -30° C. (internal temperature). A solution of 19.7 g(61.0 mmol) (1 R)-B-chlorodiisopinocampheylborane in 35 mL was addeddropwise and after the addition had ended the reaction solution wasstirred for 30 min without cooling. 15 mL of 4 N NaOH were added(temperature increase to 20° C.), the mixture was stirred for another 5min, cooled to 0° C., combined with 50 mL MTBE and stirred for 20 min.The organic phase was separated off and dried on Na₂SO₄. After theelimination of the desiccant and solvent the residue was reacted furtherwithout any purification.

Yield: 10.3 g (100% of theory)

ESI-MS: (M−H)⁻=313

Retention time (HPLC-MS): 4.2 min (method B)

11g) methyl(R)-3-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-2-hydroxy-propionate

Prepared analogously to Example 1e from 10.3 g (30.7 mmol)(R)-3-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-2-hydroxy-propionic acid and4.71 mL (64.5 mmol) thionyl chloride. The crude product obtained wasreacted further without purification.

11h) (R)-2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-1-methoxycarbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 7.12 g (34.3 mmol) 4-nitrophenyl-chloroformate in 30 mLTHF was added within 10 min to a solution of 75 mL pyridine heated to60° C. (bath temperature), the mixture was stirred for 10 min and then asolution of 10.0 g of the crude product from Example 11g in 50 mLpyridine was added dropwise. The mixture was stirred for another 1 h,combined with 6.72 g (27.4 mmol)3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and the bathtemperature was raised to 100° C. (2 h). The precipitate formed wasfiltered, the filtrate was concentrated by evaporation i. vac., theresidue was combined with 150 mL EtOAc, the organic phase was washedtwice with 50 mL of 1 M KHSO₄ solution and ten times with 50 mL of 15%K₂CO₃ solution and dried on Na₂SO₄. After the elimination of thedesiccant and solvent the residue was purified by chromatography (silicagel, EtOAc/Cyc 2:1).

Yield: 2.28 g (14% of theory)

ESI-MS: (M+H)⁺=600

Retention time (HPLC-MS): 5.4 min (method B)

11i) (R)-2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 50 mg (2.09 mmol) LiOH in 5 mL water was added to asolution of 800 mg (1.33 mmol)(R)-2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-1-methoxy-carbonyl-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 15 mL THF and the reaction mixture was stirred for 1 h at RT. Themixture was evaporated down i.vac., the residue was taken up in 50 mLwater, and 2 M HCl was added until an acidic reaction was obtained. Theprecipitate formed was filtered off, washed with water and dried.Further purification was carried out by decocting with 150 mL water,filtration and drying again.

Yield: quantitative

ESI-MS: (M+H)⁺=586

Retention time (HPLC-MS): 4.8 min (method B)

11k) (R)-1-carboxy-2-(3-ethyl-4-hydroxy-5-methyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

810 mg (1.38 mmol)(R)-2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-1-carboxy-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylatein 25 mL MeOH were combined with 80 mg of 10% Pd/C and hydrogenated atRT and 3 bar hydrogen until the reaction came to an end. The catalystwas removed by suction filtering and the solvent was concentrated byevaporation i. vac. The residue was triturated with DIPE, suctionfiltered and dried.

Yield: 639 mg (93% of theory)

ESI-MS: (M+H)⁺=496

Retention time (HPLC-MS): 3.7 min (method B)

11l)(R)-1-(3-ethyl-4-hydroxy-5-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

33 mg (0.18 mmol) 1-methyl-4-piperidin-4-yl-piperazine were added at RTto a solution of 80 mg (0.16 mmol)(R)-1-carboxy-2-(3-ethyl-4-hydroxy-5-methyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate,57 mg (0.18 mmol) TBTU and 28 μL (0.20 mmol) triethylamine in 1 mL DMFand the reaction mixture was stirred for 2 h. The reaction solution waspurified by HPLC without any further working up, the fractionscontaining the product were combined and lyophilised.

Yield: 68 mg (64% of theory)

ESI-MS: (M+H)⁺=661

Retention time (HPLC-MS): 3.0 min (method B)

The following compounds were prepared analogously from 80 mg (Example11.1) or 150 mg (Example 11.2) of(R)-1-carboxy-2-(3-ethyl-4-hydroxy-5-methyl-phenyl)-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylateand the corresponding amount of amine:

Example —R³—R⁴ Yield (%) Mass spectrum Retention time HPLC (method) 11.1

73 648 [M + H]⁺ 3.2 min (B) 11.2

48 733 [M + H]⁺ 3.0 min (B)

EXAMPLE 11.3(R)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-1-(3-ethyl-4-hydroxy-5-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

A solution of 3.7 mg (0.15 mmol) LiOH in 3 mL water was added to asolution of 73 mg (0.1 0 mmol)(R)-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-1-(3-ethyl-4-hydroxy-5-methyl-benzyl)-2-oxo-ethyl4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate(Example 11.2) in 5 mL THF and the reaction mixture was stirred for 2 hat RT. The THF was eliminated i.vac., 1 M HCl was added until an acidicreaction was obtained and the mixture was evaporated down again i.vac.The residue was taken up in DMF and purified by HPLC; the fractionscontaining the product were combined and lyophilised.

Yield: 39 mg (56% of theory)

ESI-MS: (M+H)⁺=705

Retention time (HPLC-MS): 2.9 min (method B)

The Examples that follow describe the preparation of pharmaceuticalformulations which contain as active substance any desired compound ofgeneral formula I:

EXAMPLE I

Capsules for Powder Inhalation Containing 1 mg of Active Ingredient

Composition:

1 capsule for powder inhalation contains: active ingredient  1.0 mglactose 20.0 mg hard gelatine capsules 50.0 mg 71.0 mgMethod of Preparation:

The active ingredient is ground to the particle size required forinhaled substances. The ground active ingredient is homogeneously mixedwith the lactose. The mixture is transferred into hard gelatinecapsules.

EXAMPLE II

Inhalable Solution for Respimat® Containing 1 mg of Active Ingredient

Composition:

1 puff contains: active ingredient 1.0 mg benzalkonium chloride 0.002 mgdisodium edetate 0.0075 mg purified water ad 15.0 μlMethod of Preparation:

The active ingredient and benzalkonium chloride are dissolved in waterand transferred into Respimat® cartridges.

EXAMPLE III

Inhalable Solution for Nebulisers Containing 1 mg of Active Ingredient

Composition:

1 vial contains: active ingredient 0.1 g sodium chloride 0.18 gbenzalkonium chloride 0.002 g purified water ad 20.0 mlMethod of Preparation:

The active ingredient, sodium chloride and benzalkonium chloride aredissolved in water.

EXAMPLE IV

Propellant Gas-operated Metered Dose Aerosol Containing 1 mg of ActiveIngredient

Composition:

1 puff contains: active ingredient  1.0 mg lecithin 0.1% propellant gasad 50.0 μlMethod of Preparation:

The micronised active ingredient is homogeneously suspended in themixture of lecithin and propellant gas. The suspension is transferredinto a pressurised container with a metering valve.

EXAMPLE V

Nasal Spray Containing 1 mg of Active Ingredient

Composition:

active ingredient 1.0 mg sodium chloride 0.9 mg benzalkonium chloride0.025 mg disodium edetate 0.05 mg purified water ad 0.1 mlMethod of Preparation:

The active ingredient and the excipients are dissolved in water andtransferred into a suitable container.

EXAMPLE VI

Injectable Solution Containing 5 mg of Active Substance per 5 ml

Composition:

active substance 5 mg glucose 250 mg human serum albumin 10 mgglycofurol 250 mg water for injections ad 5 mlPreparation:

Glycofurol and glucose are dissolved in water for injections (Wfl);human serum albumin is added; active ingredient is dissolved withheating; made up to specified volume with Wfl; transferred into ampoulesunder nitrogen gas.

EXAMPLE VII

Injectable Solution Containing 100 mg of Active Substance per 20 ml

Composition:

active substance 100 mg monopotassium dihydrogen phosphate = KH₂PO₄ 12mg disodium hydrogen phosphate = Na₂HPO₄*2H₂O 2 mg sodium chloride 180mg human serum albumin 50 mg Polysorbate 80 20 mg water for injectionsad 20 mlPreparation:

Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate anddisodium hydrogen phosphate are dissolved in water for injections (Wfl);human serum albumin is added; active ingredient is dissolved withheating; made up to specified volume with Wfl; transferred intoampoules.

EXAMPLE VIII

Lyophilisate Containing 10 mg of Active Substance

Composition:

Active substance 10 mg Mannitol 300 mg human serum albumin 20 mg waterfor injections ad 2 mlPreparation:

Mannitol is dissolved in water for injections (Wfl); human serum albuminis added; active ingredient is dissolved with heating; made up tospecified volume with Wfl; transferred into vials; freeze-dried.

Solvent for Lyophilisate:

Polysorbate 80 = Tween 80 20 mg mannitol 200 mg water for injections ad10 mlPreparation:

Polysorbate 80 and mannitol are dissolved in water for injections (Wfl);transferred into ampoules.

EXAMPLE IX

Tablets Containing 20 mg of Active Substance

Composition:

active substance 20 mg lactose 120 mg  corn starch 40 mg magnesiumstearate  2 mg Povidone K 25 18 mgPreparation:

Active substance, lactose and corn starch are homogeneously mixed;granulated with an aqueous solution of Povidone; mixed with magnesiumstearate; compressed in a tablet press; weight of tablet 200 mg.

EXAMPLE X

Capsules Containing 20 mg Active Substance

Composition:

active substance 20 mg corn starch 80 mg highly dispersed silica  5 mgmagnesium stearate 2.5 mg Preparation:

Active substance, corn starch and silica are homogeneously mixed; mixedwith magnesium stearate; the mixture is packed into size for 3 hardgelatine capsules in a capsule filling machine.

EXAMPLE XI

Suppositories Containing 50 mg of Active Substance

Composition:

active substance  50 mg hard fat (Adeps solidus) q.s. ad 1700 mgPreparation:

Hard fat is melted at about 38° C.; ground Active Substance ishomogeneously dispersed in the molten hard fat; after cooling to about35° C. it is poured into chilled moulds.

EXAMPLE XII

Injectable Solution Containing 10 mg of Active Substance per 1 ml

Composition:

active substance 10 mg mannitol 50 mg human serum albumin 10 mg waterfor injections ad 1 mlPreparation:

Mannitol is dissolved in water for injections (Wfl); human serum albuminis added; active ingredient is dissolved with heating; made up tospecified volume with Wfl; transferred into ampoules under nitrogen gas.

1. A compound of the formula I

wherein R¹ denotes a group of the formula

wherein R^(1.1) denotes H or H₃C—O—, R² denotes a group of the formulaII

wherein R^(2.1) denotes HO, H₃CO, H—C(O)—O or H₃C—C(O)—O— and R^(2.2)denotes C₁₋₂-alkyl or H₃CO—, R³ denotes R⁴—C₂₋₈-alkylene-NH— and R⁴denotes H, H₂N, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂—N or C₁₋₆-alkyl-O—C(O)—NH—or R³ denotes a group of the formulae

wherein R^(3.2) denotes H or C₁₋₃-alkyl, R^(3.3) denotes a free electronpair or an oxygen atom, R^(3.4) denotes H or C₁₋₃-alkyl and R⁴ denotesH, C₁₋₆-alkyl, H₂N—C₂₋₆-alkylene, C₁₋₃-alkyl-NH—C₂₋₆-alkylene,(C₁₋₃-alkyl)₂—N—C₁₋₆-alkylene, C₃₋₆-cycloalkyl-C₁₋₃-alkylene, NH₂,C₁₋₃-alkyl-NH or (C₁₋₃-alkyl)₂—N, or R⁴ denotes a group selected from

R⁴ denotes a group of the formulae

wherein X denotes C and R^(4.1) denotes H, OH or C₁₋₃-alkyl or X denotesN and R^(4.1) denotes a free electron pair or an oxygen atom, Y denotesO, S, S(O), S(O)₂, if X═N, or Y denotes S, S(O), S(O)₂, if X═C, R^(4.2)denotes H or C₁₋₃-alkyl, R^(4.3) denotes H or C₁₋₃-alkyl, R^(4.4)denotes a free electron pair or, if R^(5.2) is not H orC₁₋₃-alkyl-C(O)—, an oxygen atom, R^(5.1) denotes H, CN, OH, C₁₋₃-alkyl,C₁₋₃-alkyl-C(O)—O, C₁₋₃-alkyl-O, R^(5.1,1-)O—C(O),R^(5.1,1-)O—C(O)-C₂₋₄-alkylene or R^(5.1,1-)C(O)—C₁₋₃-alkylene-O,R^(5.1.1) denotes H, C₁₋₆-alkyl, H₂N—C(O)—C₁₋₃-alkylene,C₁₋₃-alkyl-NH—C(O)—C₁₋₃-alkylene, (C₁₋₃-alkyl)₂—N—C(O)—C₁₋₃-alkylene orC₁₋₃alkyl-O—C(O)—O—C₁₋₃alkylene, R^(5.2) denotes H, C₁₋₃-alkyl,C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkylene, C₁₋₃-alkyl-C(O),R^(5.2.1)—O—C(O)—C₁₋₃-alkylene orR^(5.2.2)—C₂₋₄-alkylene-O—C(O)—C₁₋₃-alkylene, R^(5.2.1) denotes H,C₁₋₆-alkyl, C₁₋₆-alkyl-C(O)—O—C₁₋₃-alkylene,C₁₋₃-alkyl-O—C(O)—O—C₁₋₃-alkylene,C₃₋₇-cycloalkyl-O—C(O)—O—C₁₋₃-alkylene, H₂N—C(O)—C₁₋₃-alkylene,C₁₋₃-alkyl-NH—C(O)—C₁₋₃-alkylene, (C₁₋₃-alkyl)₂—N—C(O)—C₁₋₃-alkylene orR^(5.2.1,1-)C(O)—C₁₋₃-alkylene and R^(5.2.1.1) denotes a group selectedfrom

R^(5.2.1) denotes a group selected from

R^(5.2.2) denotes H₂N, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂—N, C₁₋₃-alkyl-O orC₁₋₃-alkyl-O—C₂₋₄-alkylene-O, or R^(5.2.2) denotes a group selected from

with the proviso that R³ and R⁴ are not bound to one anothersimultaneously via an N atom, or a tautomer or salt thereof.
 2. Acompound of the formula I according to claim 1, wherein R¹ denotes agroup of the formula

wherein R^(1.1) denotes H or H₃C—O—, R² denotes a group of the formulaII

wherein R^(2.1) denotes HO, H₃CO, H—C(O)—O or H₃C—C(O)—O— and R^(2.2)denotes C₁₋₂-alkyl or H₃CO—, R³ denotes R⁴—C₂₋₈-alkylene-NH— and R⁴denotes H₂N, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂—N or C₁₋₆-alkyl-O—C(O)—NH, orR³ denotes a group of the formulae

wherein R^(3.2) denotes H, R^(3.3) denotes a free electron pair or anoxygen atom, R^(3.4) denotes H or C₁₋₃-alkyl, R⁴ denotes H, C₁₋₆-alkyl,H₂N—C₂₋₆-alkylene, C₁₋₃-alkyl-NH—C₂₋₆-alkylene,(C₁₋₃-alkyl)₂—N—C₁₋₆-alkylene, C₃₋₆-cycloalkyl-C₁₋₃-alkylene, H₂N,C₁₋₃-alkyl-NH or (C₁₋₃-alkyl)₂—N, or R⁴ denotes a group selected from

R⁴ denotes a group of the formulae

wherein X denotes C and R^(4.1) denotes H, OH, C₁₋₃-alkyl or X denotes Nand R^(4.1) denotes a free electron pair or an oxygen atom, Y denotes O,S, S(O), S(O)₂, if X═N, or Y denotes S, S(O), S(O)₂, if X═C, R^(4.2)denotes H, R^(4.3) denotes H or C₁₋₃-alkyl, R^(4.4) denotes a freeelectron pair or, if R^(5.2) is not H or C₁₋₃-alkyl-C(O)—, an oxygenatom, R^(5.1) denotes H, CN, OH, C₁₋₃-alkyl, C₁₋₃-alkyl-C(O)—O,C₁₋₃-alkyl-O, R^(5.1.1)—O—C(O), R^(5.1,1)—O—C(O)—C₂₋₄-alkylene orR^(5.1,1)—O—C(O)—C₁₋₃-alkylene-O, R^(5.1.1) denotes H, C₁₋₆-alkyl,H₂N—C(O)—C₁₋₃-alkylene, C₁₋₃-alkyl-NH—C(O)—C₁₋₃-alkylene,(C₁₋₃-alkyl)₂—N—C(O)—C₁₋₃-alkylene or C₁₋₃-alkyl-O—C(O)—O—C₁₋₃-alkylene,R^(5.2) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkylene, C₁₋₃-alkyl-C(O),R^(5.2.1)—O—C(O)—C₁₋₃-alkylene orR^(5.2.2)—C₂₋₄-alkylene-O—C(O)—C₁₋₃-alkylene, R^(5.2.1) denotes H,C₁₋₆-alkyl, C₁₋₆-alkyl-C(O)—O—C₁₋₃-alkylene,C₁₋₃-alkyl-O—C(O)—O—C₁₋₃-alkylene,C₃₋₇-cycloalkyl-O—C(O)—O—C₁₋₃-alkylene, H₂N—C(O)—C₁₋₃-alkylene,C₁₋₃-alkyl-NH—C(O)—C₁₋₃-alkylene, (C₁₋₃-alkyl)₂—N—C(O)—C₁₋₃-alkylene orR^(5.2.1,1)—C(O)—C₁₋₃-alkylene and R^(5.2.1.1) denotes a group selectedfrom

R^(5.2.1) denotes a group selected from

R^(5.2.2) denotes H₂N, C₁₋₃-alkyl-NH, (C₁₋₃-alkyl)₂—N, C₁₋₃-alkyl-O orC₁₋₃-alkyl-O—C₂₋₄-alkylene-O, or R^(5.2.2) denotes a group selected from

with the proviso that R³ and R⁴ are not bound to one anothersimultaneously via an N atom, or a tautomer or salt thereof.
 3. Acompound of the formula I according to claim 1, wherein R¹ denotes agroup of the formula

R² denotes a group selected from

R³ denotes R⁴—C₂₋₈-alkylene-NH— and R⁴ denotes H, H₂N, (C₁₋₃-alkyl)₂—Nor C₁₋₄-alkyl-O—C(O)—NH—, or R³ denotes a group selected from

and R⁴ denotes H, C₁₋₆-alkyl, (C₁₋₃-alkyl)₂—N—C₁₋₆-alkylene,C₃₋₆-cycloalkyl-C₁₋₃-alkylene or (C₁₋₃-alkyl)₂—N, or R⁴ denotes a groupselected from

R⁴ denotes a group selected from

wherein Y denotes O, S, S(O), S(O)₂, R^(4.4) denotes a free electronpair or, if R^(5.2) is not H or C₁₋₃-alkyl-C(O)—, an oxygen atom,R^(5.1) denotes H, CN, OH, C₁₋₃-alkyl, C₁₋₃-alkyl-C(O)—O, C₁₋₃-alkyl-O,R^(5.1,1)—O—C(O), R^(5.1,1)—O—C(O)—C₂₋₄-alkylene orR^(5.1,1)—O—C(O)—C₁₋₃-alkylene-O, R^(5.1.1) denotes H, C₁₋₆-alkyl,H₂N—C(O)—C₁₋₃-alkylene, C₁₋₃-alkyl-NH—C(O)—C₁₋₃-alkylene,(C₁₋₃-alkyl)₂—N—C(O)—C₁₋₃-alkylene or C₁₋₃-alkyl-O—C(O)—O—C₁₋₃-alkylene,R^(5.2) denotes H, C₁₋₃-alkyl, cyclopropyl, cyclopropyl-methylene,C₁₋₃-alkyl-C(O), R^(5.2.1)—O—C(O)—C₁₋₃-alkylene orR^(5.2.2)—C₂₋₄-alkylene-O—C(O)—C₁₋₃-alkylene, R^(5.2.1) denotes H,C₁₋₆-alkyl, C₁₋₆-alkyl-C(O)—O—C₁₋₃-alkylene,C₁₋₃-alkyl-O—C(O)—O—C₁₋₃-alkylene, (C₁₋₃-alkyl)₂—N—C(O)—C₁₋₃-alkylene orR^(5.2.1,1)—C(O)—C₁₋₃-alkylene and R^(5.2.1.1) denotes a group selectedfrom

R^(5.2.1) denotes a group selected from

R^(5.2.2) denotes (C₁₋₃-alkyl)₂—N, C₁₋₃-alkyl-O orC₁₋₃-alkyl-O—C₂₋₄-alkylene-O, or R^(5.2.2) denotes a group selected from

with the proviso that R³ and R⁴ are not bound to one anothersimultaneously via an N atom, or a tautomer or salt thereof.
 4. Acompound of the formula I according to claim 1, wherein R¹ denotes agroup of the formula

R² denotes a group selected from

R³-R⁴ together denote a group selected from

or a tautomer or salt thereof.
 5. A compound of the formula I accordingto claim 1, wherein R¹ denotes a group of the formula

R² denotes a group selected from

R³-R⁴ together denote a group selected from

or a tautomer or salt thereof.
 6. A compound of the formula I accordingto claim 1, selected from the group consisting of: No. Structure (16)

(17)

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or a tautomer or salt thereof.
 7. A physiologically acceptable salt of acompound according to claim 1, 2, 3, 4, 5, or
 6. 8. A pharmaceuticalcomposition comprising a compound of the formula I, according to claim1, 2, 3, 4, 5 or 6, or a physiologically acceptable salt thereof,optionally together with one or more inert carriers and/or diluents. 9.A method for treating or reducing the incidence of headaches whichmethod comprises the administration, to a person who is suffering from aheadache or is prone to suffer from headaches, a therapeutically orprophylactically effective amount of a compound of the formula I,according to claim 1, 2, 3, 4, 5 or 6, or a pharmaceutically acceptablesalt thereof.
 10. A method for treating non-insulin-dependent diabetesmellitus (NIDDM) which method comprises the administration, to a personwho is suffering from NIDDM, a therapeutically effective amount of acompound of the formula I, according to claim 1, 2, 3, 4, 5 or 6, or apharmaceutically acceptable salt thereof.